Download Infection, immunoregulation, and cancer

Graham A. W. Rook
Angus Dalgleish
Infection, immunoregulation, and
cancer
Authors’ addresses
Graham A. W. Rook1, Angus Dalgleish2
1
Department of Infection, University College London (UCL),
London, UK.
2
St George’s Healthcare NHS Trust, London, UK.
Summary: As man has moved rapidly from the hunter–gatherer environment to the living conditions of the industrialized countries, the incidences of some cancers have increased alarmingly. Recent increases are
usually attributed to dietary changes or to altered exposures to putative
carcinogens associated with the modern lifestyle. However, the changes
in cancer incidence parallel similar increases in non-neoplastic chronic
inflammatory disorders (inflammatory bowel disease, allergies, and
autoimmunity), and the epidemiology is often strikingly similar. This
parallel is worth exploring, because the increases in chronic inflammatory disorders are at least partly explained by immunoregulatory defects
resulting from diminished exposure to microorganisms that co-evolved
with mammals and developed a role in driving immunoregulatory circuits (the hygiene hypothesis). Dysregulated chronic inflammation can
drive oncogenesis and also provides growth and angiogenic factors that
enhance the subsequent proliferation and spread of tumor cells. Thus, a
modern failure to downregulate inappropriate inflammation could
underlie increases in some cancers in parallel with the increases in
chronic inflammatory disorders. This possibility is supported by recent
work showing that in some circumstances regulatory T cells protect
against cancer, rather than aggravating it, as previously assumed. A
greater understanding of these interactions might pave the way to
improved microbe-based immunotherapies.
Correspondence to:
Graham A. W. Rook
Department of Infection
University College London (UCL)
46 Cleveland Street
London W1T 4JF, UK
Tel.: +44 20 7679 9489
Fax: +44 20 7607 0016
e-mail: [email protected]
Acknowledgements
The authors declare no conflicts of interest.
Keywords: cancer, immunoregulation, Treg, hygiene hypothesis, infection, IL-10,
TGF-b
Introduction
Immunological Reviews 2011
Vol. 240: 141–159
Printed in Singapore. All rights reserved
2011 John Wiley & Sons A/S
Immunological Reviews
0105-2896
As man has moved rapidly from the hunter–gatherer environment to the living conditions of the rich industrialized countries, the incidences of some cancers have increased
alarmingly. Some cancers (< 20%) are attributed to oncogenic changes or chronic inflammation caused by infections,
but most of the recent increases have been attributed by
oncologists to dietary changes or to altered exposures to putative carcinogens associated with the modern lifestyle. Interestingly, the changes in cancer incidence have been paralleled by
even larger increases in a number of non-neoplastic chronic
inflammatory disorders (inflammatory bowel disease, allergies, and autoimmunity), and the details of the epidemiology
are often strikingly similar. This parallel is worth exploring,
because chronic inflammation can contribute to oncogenesis
2011 John Wiley & Sons A/S • Immunological Reviews 240/2011
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Rook & Dalgleish Æ Infection, immunoregulation, and cancer
and often provides growth and angiogenic factors which
enhance the proliferation and spread of tumor cells. A failure
to regulate inflammation could underlie not only the chronic
inflammatory disorders but also some cancers.
If this hypothetical parallel were found to be real, it would
provide important pathogenetic clues, because a significant
part of the increase in chronic inflammatory disorders is
now thought to be attributable to diminished exposure to a
range of microorganisms and parasites that either co-evolved
with humans or accompanied humans from at least as far
back as the Paleolithic era. These organisms have been present throughout human evolution as commensals (notably in
the intestinal microbiota), environmental ‘pseudocommensals’, causative agents of subclinical infections or asymptomatic carrier states, and helminth infections. Modern revisions
of the ‘Hygiene’ or ‘Old Friends’ hypothesis suggest that
such organisms have been tasked by co-evolutionary processes with establishing the ‘normal’ levels of immunoregulation within the immune system. Therefore, when exposure
to the Old Friends is reduced, there is a relative failure to
terminate inappropriate inflammatory responses, leading to
increases in the chronic inflammatory disorders listed above
(1). Here, in view of the crucial roles of inflammation in
cancer, we explore the potential relevance of this concept to
the changing incidences of several cancers in developed
countries.
Infection as a cause of cancer
There have been numerous excellent reviews of the role of
infections as causes of cancer (2–6). In contrast, there has
been much less discussion of the possible roles of infections
in the prevention of cancer, and in this review we seek to
explore both aspects in parallel.
Table 1 illustrates most of the organisms associated with cancer development, classified as far as possible according to how
cancer is promoted (though there is much overlap). One
purpose of the table is to demonstrate that inflammation is a
crucial aspect of oncogenesis attributable to infection, while
very few organisms cause cancer by direct infection and transformation of target cells. The lymphotropic oncogenic viruses
Epstein–Barr virus (EBV), human herpesvirus 8 (HHV8), and
human T-lymphotropic virus 1 (HTLV-1), are examples of the
latter, and these viruses directly infect a subset of lymphoid
cells, which they can then transform either directly or
indirectly by transactivation of oncogenes, as in the case of
HTLV-1.
Little is known about the role in cancer causation of the
truly intracellular infections that form the major focus of this
Table 1. The major infectious agents that trigger cancer
Mechanism
Infect and transform lymphoid cells
Transformation
Inflammation and partial integration
Chronic inflammation and oncogenic proteins
Chronic stimulation of lymphocytes by
pathogen antigens and ⁄ or autoantigens
Chronic inflammation
Chronic inflammation; possible associations
Immunosuppression
*
Organism
Cancer
Epstein–Barr virus (EBV)
Human Herpesvirus 8 (HHV8)
Human T-lymphotropic virus 1 (HTLV-1)
HPV
HBV
Hepatitis C virus (HCV)
Helicobacter pylori
Campylobacter jejuni Borrelia burgdorferi
Chlamydia psittaci
Hepatitis C virus (HCV)
Bacteroides fragilis (enterotoxigenic)
Malaria (cofactor)
Tuberculosis
Schistosomiasis
Liver flukes
Salmonella spp.
Helicobacter pylori
Propionibacterium acnes?
Mycoplasma spp. ?
?? unknown prostatitis ??
HIV
References
*
Burkitt’s lymphoma
Kaposi sarcoma
T-cell leukemia
Cervical cancer
Hepatocellular carcinoma
Hepatocellular carcinoma
Gastric lymphoma
Immunoproliferative small intestinal dis.
Cutaneous lymphoma
Ocular lymphoma
Spleen lymphoma
Colorectal cancer
Burkitt’s lymphoma
Lung cancer
Bladder cancer
Cholangiocarcinoma
Gallbladder cancer
Gastric and esophageal adenocarcinoma
Prostate
Prostate
Prostate
EBV+ CNS lymphomas
HHV8+ sarcoma (Kaposi)
HPV+ ano-genital cancers
(4)
(2)
(2)
(4)
(3)
(29)
(3)
(30)
(3)
(146, 147)
(7)
(9, 10)
(2, 5)
(5)
(8)
(113, 115)
(148)
(149)
(4)
EBV also associated with nasopharyngeal carcinoma, Hodgkin lymphoma and non-Hodgkin lymphoma.
C. jejuni produce CdtB (cytolethal distending toxin B) that causes direct DNA damage.
HCV also encodes oncogenic proteins.
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Rook & Dalgleish Æ Infection, immunoregulation, and cancer
volume, though there are exceptions. Malaria can act as a cofactor for EBV-induced oncogenesis, because Plasmodium falciparum antigens such as PfEMP1 can induce reactivation of EBV
(7). The increased viral load and the concomitant polyclonal
B-cell activation with enhanced B-cell survival may augment
the risk of endemic Burkitt’s lymphoma in children living in
malaria-endemic areas (7). Similarly, although gallbladder
cancer is relatively rare, the highest incidences are seen in
populations where chronic infections like Salmonella typhi and S.
paratyphi are prevalent, though obesity and multiparity are also
consistently associated (8). More controversially, it has been
reported that autopsies of patients with lung cancer frequently
reveal the simultaneous presence of tuberculous lesions in the
lungs (9). This observation might be meaningful, because it
has been reported that there is an increased risk of lung cancer
following a diagnosis of TB among farmers in Xuanwei,
China. The risk was greatest within 5 years of diagnosis but
remained elevated (approximately threefold) for more than
10 years. This association was seen in men and women and
was not due to confounding effects of tobacco use or indoor
environmental smoke (10). Nevertheless, the situation is
likely to be more complex, because M. tuberculosis has immunoregulatory effects that differ according to whether latent or
progressive infection has developed, and this is discussed
later.
In view of the paucity of direct evidence for involvement of
intracellular infections in either preventing or causing oncogenesis (excluding viruses which are outside the remit of this
article), certain other organisms will be used to illustrate their
potential role. In particular, the involvement of Helicobacter pylori
in gastric lymphoma and gastric and esophageal adenocarcinoma is of striking interest. Most H. pylori localize within the
gastric mucus layer and do not directly interact with host cells.
However, some organisms adhere to gastric epithelial cells
and occasionally are internalized by these cells. Using fluorescent in situ hybridization (FISH) with probes for H. pylori 16S
rRNA and cagA, H. pylori was detected inside metaplastic, dysplastic, and neoplastic epithelial cells (11). These findings are
compatible with the view that an intracellular location is
involved in the carcinogenic effect and fits with the observation that therapy aimed at eliminating H. pylori can induce
regression of precancerous lesions (11).
Chronic inflammation
Inflammation is present in tumors and is fundamental to their
development and spread. Inflammation can enhance mutation
(12), growth, vascularization (13), and metastasis (Fig. 1).
2011 John Wiley & Sons A/S • Immunological Reviews 240/2011
Fig. 1. Some potential roles of infection in preventing and causing
cancer (excluding direct transformation, which is discussed briefly in
the main text). Epidemiological studies indicate that transient infection
may provide some protection against cancer. However, chronic infection
leading to chronic inflammation can initiate oncogenesis, and also, by
subsequently providing growth and angiogenic factors, potentiate existing cancers.
Tumor necrosis factor-a (TNF-a) may be particularly important (14), and it has been found to be secreted by a wide variety of tumor cells, including B and T-cell lymphoma, myeloid
and lymphoid leukemias, carcinomas of the breast, colon,
lung, ovary, pancreas, prostate, cervix, and glioblastoma, and
neuroblastoma (reviewed in 15). There have been excellent
recent reviews of these issues, which will therefore only be
outlined briefly here (14–18).
Background: inflammation in cancer
First, tumors contain ‘smoldering’ inflammation (including
release of TNF-a, as discussed above) that is not obviously
related to any external inflammatory stimulus (17). This is
partly because several important oncogenes such as RAS and
MYC activate signaling pathways involved in inflammation
(17). In addition, commonly seen mutations in tumor-suppressor genes such as Von Hippel-Lindau tumor suppressor
(VHL), transforming growth factor-b (TGF-b), and phosphatase and tensin homologue (PTEN), can all lead to increased
activation of transcription factors involved in inflammation
and vascularization, particularly nuclear factor-jB (NF-jB),
hypoxia inducible factor 1a (HIF-1a), and signal transducer
and activator of transcription 3 (STAT3) (19). Moreover, many
carcinomas secrete factors that upregulate fibronectin and
recruit vascular endothelial growth factor receptor 1 (VEGFR1)-positive hematopoietic progenitors and inflammatory
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Rook & Dalgleish Æ Infection, immunoregulation, and cancer
cells to sites of tumor growth. These cells may also secrete factors that directly activate recruited myeloid cells to produce
tumor-promoting cytokines such as TNF-a and IL-6 (14, 20).
Increased rates of DNA damage and defective repair
The mutation rate in inflamed tissues is higher than in normal
tissues, though lower than in tumors (21). A number of
mechanisms and pathways have been implicated in the
increased mutation rate. Growth factors, cytokines, and
chemokines produced by inflammatory cells and by the tumor
itself induce increased expression of transcription factors such
as c-Myc and also increase the activity of NF-jB, HIF-1a, and
STAT3. These transcription factors alter the expression of hundreds of target genes related to cell growth, apoptosis, invasion, and inflammation. These processes accelerate the
intrinsic mutation rate in cancer cells, at least partly by
increasing levels of reactive oxygen species (ROS) and nitrogen species.
ROS released from inflammatory cells can cause double
strand breaks in the DNA of cancer cells. Moreover nitric
oxide (NO) and the inflammatory cytokine interleukin-6 (IL6) increase the activity of DNA methyltransferase, resulting in
extensive methylation of cytosine bases including those in
CpG islands that can be located in promoters. This can lead to
the silencing of promoters and loss of expression of the genes
encoding essential mismatch-repair genes, such as hMLH1.
This epigenetic change leads in turn to faulty DNA repair,
resulting in microsatellite insertions and deletions within the
coding regions of tumor suppressor genes. (microsatellites are
normal, common, repeated sequences of DNA from 1to 6 bp,
often located in promoter regions). The consequent microsatellite instability in tumor suppressor genes can lead to uncontrolled cell division and tumor growth (22). Among the genes
that contain microsatellites in their coding regions are those
encoding the TGF-b receptor 2, insulin-like growth factor 2
receptor, and BCL2-associated X protein (BAX).
Another intriguing mechanism of DNA damage is ectopic
expression of activation-induced cytidine deaminase (AID).
This DNA ⁄ RNA editing enzyme normally induces hypermutation of the immunoglobulin loci in B cells. However, it can be
ectopically induced in tumors by a variety of inflammatory
cytokines. When ectopically expressed, rather than targeting
immunoglobulin loci in B cells, AID produces mutations and
translocations through induction of double strand breaks in
the DNA of other cell types. Ultimately chromosomal instability results in abnormal segregation of chromosomes and aneuploidy (12).
144
Angiogenesis and metastasis
In healthy adults, the growth of new vessels is largely confined
to the female genital tract and to sites of wound repair. It is
regulated by a balance between angiogenic factors such as vascular endothelial growth factor A (VEGFA), fibroblast growth
factors (FGFs), platelet-derived growth factor (PDGF), and
epidermal growth factor (EGF), and inhibitors of angiogenesis
such as thrombospondin 1, angiostatin, endostatin, and
tumstatin. The inflammatory cascades in tumors (Fig. 1),
whether the intrinsic effects of the oncogenic mutations in the
tumor cells themselves (17), secondary release of mediators
from recruited inflammatory cells (20), or inflammation due
to infection (23), can all lead to an imbalance, where inappropriate angiogenesis is encouraged and metastasis is facilitated
(24–26). In a classic experiment, fibrosarcoma cells showed
enhanced metastasis to the lungs in the presence of exogenous
TNF, while neutralization of endogenous TNF led to a significant decrease in the number of pulmonary metastases (26,
27). Angiogenesis is further promoted by infiltration of
monocytes expressing tyrosine kinase with immunoglobulinlike and EGF-like domains 2 (TIE-2). These TIE-2-expressing
monocytes (TEMs) constitute a small pro-angiogenic monocyte subset that circulates in the mouse and human peripheral
blood. TIE-2 is a cell-surface receptor for angiopoietins, and
these cells are preferentially recruited to tumors and other sites
of angiogenesis (18).
Additional oncogenic effects of infection
All the mechanisms described in the previous section can
occur in tumors in the absence of infection. In the current
context, the important point is that infections induce similar
changes and so can initiate and promote tumors. Moreover
infections can encourage oncogenesis by additional mechanisms described in this section.
Infection-induced DNA abnormalities
The immune response to infection can lead to local release of
ROS and nitrogen species, thereby increasing the likelihood of
oncogenic mutations. Interestingly, methylation changes
affecting CpG islands in promoters of tumor suppressor genes
like those discussed above are also found in a model of Helicobacter infection (28).
Chronic stimulation of lymphoid cells
Chronic stimulation by microbial antigens or autoantigens is
associated with a distinct subset of extranodal lymphomas
2011 John Wiley & Sons A/S • Immunological Reviews 240/2011
Rook & Dalgleish Æ Infection, immunoregulation, and cancer
arising from B cells of the marginal zone of mucosa-associated lymphoid tissue (MALT) or of the spleen (3, 29, 30).
The implicated organisms include H. pylori, Campylobacter jejuni,
Borrelia burgdorferi, Chlamydia psittaci, and hepatitis C virus
(HCV). For example, H. pylori-infected gastric mucosal cells
produce proinflammatory cytokines (such as lymphotoxin
beta) and B-cell homing factors (such as BCA-1), leading to
the emergence of MALT in the gastric mucosa. While some
of the chronic stimulation is likely to be attributable to ongoing responses to microbial antigens, in several cases it seems
that the major stimulus comes from an autoimmune response
triggered by the infection. For example, neoplastic B cells
from gastric MALT lymphoma are not specific for H. pylori
antigens but rather for autoantigens found in the gastric
mucosa (3). These autoreactive B cells are thought to receive
cognate help from H. pylori-specific T cells displaying crossreactivity with gastric autoantigens (31, 32). Indeed autoimmunity, even when not directly attributable to a known
infection (e.g. Sjögren’s syndrome) is associated with an
increased risk of lymphomas. Thus, several mechanisms may
account for the finding that in at least 60% of patients, eradication of H. pylori can cause regression of low-grade MALT
lymphoma, and of early stage high-grade lymphomas of the
stomach (33). These mechanisms include reduction in bacterial antigen load, removal of an ‘adjuvant’ stimulus for
autoimmunity, and elimination of abnormally functioning H.
pylori-infected cells.
Similar arguments apply to several of the other organisms
implicated in the induction of extranodal lymphomas. C. jejuni
is associated with Guillain–Barré syndrome, which is caused
by cross-reactive antibodies that bind both to C. jejuni lipooligosaccharides and to gangliosides in the nervous system
(34). Similarly, the OspA protein of B. burgdorferi is structurally
homologous to human lymphocyte function antigen-1
(LFA1) and may play a role in the autoimmune manifestations
and chronic activation of the immune system that leads occasionally to lymphoma (35).
Damage, atrophy, metaplasia, dysplasia, and cancer
A further mechanism is involved when chronic infections lead
to chronic tissue damage. Detailed histopathological analysis
reveals the sequence of events that occurs in H. pylori-induced
adenocarcinoma of the stomach. First there is chronic active
non-atrophic gastritis, which is followed by focal loss of
glands (atrophy) particularly at the antrum-corpus junction,
with fibrous stromal tissue replacing the lost glands. Next
there is metaplasia, with the appearance of cells initially
2011 John Wiley & Sons A/S • Immunological Reviews 240/2011
resembling various types of differentiated small intestinal epithelial cells and later resembling colonic mucosa. These events
might be an early phase of dysplasia. Dysplasia is characterized
by atypical changes in nuclear morphology and tissue architecture. At some point, adenocarcinoma develops in these
lesions. Some investigators believe that the initial stages of
inflammation and atrophy create an abnormal microenvironment favoring engraftment of bone marrow-derived stem cells
(BMDCs) that replace the depleted local tissue stem cells.
These BMDCs are in a distinct epigenetic state and seem susceptible to mutation and deviation away from the pathway of
complete differentiation, resulting in progressive loss of differentiation, uncontrolled replication, and eventual neoplastic
invasive behavior (36). If this is correct, then infectioninduced chronic inflammation can cause cancer by attrition of
local stem cells, and their replacement with more dysplasiasusceptible BMDCs.
Infections may also reduce cancer
In addition to contributing oncogenic effects in the ways
described above, infections may also reduce the risk of cancer
(Fig. 1). The mechanisms fall into three broad categories. First,
infection might boost the host’s own immune response to
cancers because of adjuvant and immunostimulatory effects.
Second, cross-reactivity between microorganisms and tumor
antigens may lead to the priming of anti-tumor effector cells.
Third, infections can modulate immunoregulatory circuits, as
recognized in relation to the Hygiene or Old Friends hypothesis. These three mechanisms are discussed below. It is not
always possible to know which particular one is involved, and
it is likely that many infections induce more than one of
them.
Adjuvant effects
Although chronic infection, by causing chronic inflammation,
is likely to drive oncogenesis, transient exposure to microbial
components such as endotoxin (LPS) or transient infections
would be expected to enhance immune responses (Fig. 1). In
the mid-19th century, Coley (37) had noted remission of cancer in patients developing severe infections, and he attempted
to use bacterial extracts as a therapy, with some evidence of
success. This work inspired an epidemiological study of people developing melanomas. The study concluded that the risk
of melanoma was inversely related to the numbers of their
recorded infections, particularly when accompanied by high
fevers (38). Patients with histories of one, two to three and
four or more infections had odds ratios of 0.66, 0.63, and
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Rook & Dalgleish Æ Infection, immunoregulation, and cancer
0.32 respectively, and the trend was statistically significant
(P = 0.004) (38).
LPS, like many microbial components, is a powerful adjuvant. This quality has been thought to explain why workers in
the cotton industry in Shanghai have reduced incidences of
several cancers. Their heavy exposure to LPS might be protective against cancers of the esophagus, stomach (39), breast
(40), and lung (41). Similarly, dairy workers, who are
exposed to a multitude of microbial components including
LPS, have been shown to have lower incidence of lung cancer
(42). In the 1970s, a number of authors claimed that BCG
vaccination protected against leukemia and other hematological tumors, though the validity of the findings remains uncertain (43). To date, one can only speculate as to what effect
latent tuberculosis, affecting one third of the world’s population, has on the incidence of cancer.
Cross-reactivity
It appears that glycosylation changes are early consequences of
oncogenesis, and glycoproteins on tumor cells bear oligosaccharides that are markedly different from those found on proteins produced by normal cells (44). It is suggested that these
may sometimes resemble the oligosaccharide structures of
bacteria (45), with more exposed galactose, N-acetylgalactosamine, and mannose (Fig. 1). This may go some way to
explain why bacterial infections may be protective in cancer,
as they might prime immune responses to cross-reactive
epitopes on tumor cells.
Another documented cross-reactive antigen is the HERVK-MEL epitope expressed in many melanomas. It is encoded
by a human endogenous retrovirus of the HERV-K family.
Sequences predicted to cross-react with this epitope were
identified in BCG, vaccinia virus used for the smallpox vaccine, and the 17D yellow fever vaccine, all of which appear to
afford some protection against development of melanoma
(45–47).
Modulation of immunoregulatory circuits
It was pointed out above that dairy workers might be protected from ⁄ have lower risk of developing lung cancer (42).
An adjuvant effect of LPS is a possible explanation, but others
may be more relevant. Exposure to cowsheds also protects
from allergic disorders (48), and this observation forms one
of the strongest epidemiological findings underpinning the
Hygiene hypothesis, outlined in the Introduction. One might
speculate that the ‘cowshed’ effect downregulates Th2
responses, terminates inappropriate chronic (potentially
146
oncogenic) inflammation, and so simultaneously reduces
oncogenesis, and improves the potential for Th1-dominated
anti-cancer responses. The implications of the Hygiene
hypothesis for cancer are expanded in the next section.
Hygiene hypothesis
The Hygiene hypothesis seeks to explain the rapid simultaneous increases in the incidences of several types of chronic
inflammatory disease in the rich developed countries. These
include autoimmunity [e.g. multiple sclerosis (MS) and Type
1 diabetes] and inflammatory bowel diseases (IBDs) (e.g. Crohn’s disease and ulcerative colitis) (49). All of these chronic
inflammatory disorders show evidence of defective immunoregulation. Regulatory defects have been found in individuals
suffering from allergic disorders (50), some autoimmune diseases (51, 52), and probably in IBD too (53, 54). This suggests that in developed countries there is a generalized defect
in regulation of the immune system that is manifested in different individuals as a failure to terminate inappropriate
responses to allergens (allergy), self (autoimmunity such as
MS or Type 1 diabetes), or gut contents (IBD). This can be
explained by an environmental effect operating at the population level, with superimposed genetic effects operating at the
level of the individual (Fig. 2). We know that a generalized
dysfunction of immunoregulatory mechanisms can lead to
simultaneous increases in these diverse types of pathology,
because genetic defects of forkhead box protein 3 (Foxp3), a
transcription factor that plays a crucial role in the development
and function of regulatory T cells (Tregs), leads to a syndrome
known as X-linked autoimmunity–allergic dysregulation syndrome that includes aspects of allergy, autoimmunity, and
enteropathy (55). A recent reformulation of the Hygiene
hypothesis (Old Friends Hypothesis) suggests that certain
organisms that were constantly present throughout mammalian evolutionary history had to be tolerated and so co-evolved
a role in driving regulatory pathways within the immune system. The depletion of these organisms from the modern environment is thought to be contributing to the increase in
immunoregulatory disorders (1).
The organisms involved in the Hygiene hypothesis
Common infections of childhood do not protect against allergies (56–58), Type 1 diabetes (59), or IBD (60–62). Rather
epidemiological, experimental, and clinical studies have indicated that the important organisms in this context are relatively benign organisms such as lactobacilli, helminths,
orofecally transmitted infections inducing carrier states, and
2011 John Wiley & Sons A/S • Immunological Reviews 240/2011
Rook & Dalgleish Æ Infection, immunoregulation, and cancer
Fig. 2. The Hygiene or Old Friends hypothesis. The organisms with which mammals co-evolved (see Fig. 3) had to be tolerated, and mammals are
now in state of evolved dependence on their ability to drive immunoregulatory pathways. In developed countries, immunoregulation is therefore
decreased, and gene–environment interactions cause a subset of people living in developed countries to develop chronic inflammatory disorders. The
nature of the disorder (if any) depends on the genetic background of the individual.
Table 2. Some organisms implicated in the ‘Old Friends’ hypothesis
Organism
References
Hepatitis A virus
Helminths
Helicobacter pylori
Salmonella
Gut microbiota
Mycobacterium tuberculosis
Toxoplasma gondii
(unknown ? microbial)*
(150, 151)
(152, 153)
(117)
(154)
(123, 155)
(156, 157)
(57, 151, 158)
(48, 159)
*
Protection from cowsheds and homes contaminated by animal feces.
saprophytes from mud and untreated water (1). All have
long-standing associations with humans but have become
depleted by modern lifestyles. These organisms are listed and
referenced in Table 2. They were all present from very early in
human evolution and became depleted during the second epidemiological transition: during industrialization, the construction of modern cities, concrete, tarmac roads, and
separation from mud animals and feces that had always previously provided contact with them (Fig. 3).
Pro-inflammatory effects of previously beneficial genetic
factors
The depletion of regulation-inducing organisms leads to a further complication. In the developed countries, genetic factors
that were not previously causing disease can assume negative
2011 John Wiley & Sons A/S • Immunological Reviews 240/2011
roles when the Old Friends are removed. In areas with the
highest burdens of immunoregulation-inducing organisms,
accumulation of compensatory single nucleotide polymorphisms (SNPs) or other genetic variants tended to increase
release of pro-inflammatory cytokines (63–65) or enabled
enhanced Th2 responses to help control parasite burdens
(66). However, as soon as the immunoregulatory organisms
(Figs 2 and 3) are removed, these SNPs lead to exaggerated
responses, and become risk factors for chronic inflammatory
disorders (Fig. 4).
Hygiene hypothesis and cancer
As summarized above, the Hygiene hypothesis suggests that
the modern lifestyle is leaving the immune system with inadequate immunoregulatory mechanisms, causing, in some individuals, increased susceptibility to a variety of chronic
inflammatory disorders. As many cancers are increasing in
incidence too, it is interesting to speculate about a possible
connection. It is usually assumed that cancer is associated with
excessive immunoregulation rather than too little, because
many experimental systems have shown detrimental effects of
Tregs in established tumors. However in view of the clear role
of inflammation in oncogenesis, there is the obvious possibility that mechanisms described by the Old Friends Hypothesis
may be protective by terminating inappropriate inflammation,
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Rook & Dalgleish Æ Infection, immunoregulation, and cancer
Fig. 3. The Darwinian background to the Hygiene or Old Friends hypothesis. The organisms implicated by epidemiology, clinical studies, in vitro
experiments, and animal models are shown highlighted in bold font on the right. These organisms accompanied man at least as far back as the Paleolithic era and were part of mammalian evolutionary history. They were still present, often in larger quantities, after the first epidemiological transition
(Neolithic). Epidemiological studies indicate that the new sporadic infections picked up from domesticated animals following animal husbandry in
the Neolithic are not so relevant. The important organisms were progressively lost from the start of the second epidemiological transition in the early
19th century.
Factors not usually sufficient to cause disease
present from the
paleolithic
on their role in induction
of immunoregulation
Genetics
Environmental triggers
Compensatory SNP or alleles
1) pro-inflammatory cytokines
2) IgE
Delayed exposure to
viruses ?
Diet, obesity
progressively from mid
18th C as contact with
soil, animals and faeces
diminished
Potential susceptibility to Th1/
Th17 or Th2 disorders in the
Vit D deficiency,
Pollutants (dioxins) etc
Allergies, MS, IBD,
type 1 diabetes etc
and some cancers?
Fig. 4. The additional effects of compensatory single nucleotide polymorphisms (SNPs) and of aggravating environmental changes. In parts of
the world with high levels of immunoregulatory Old Friends, there has been selection for compensatory SNPs that restores the inflammatory response.
This has established an equilibrium that is disturbed when the Old Friends are lost during the second epidemiological transition. The same SNPs then
become risk factors for chronic inflammatory disorders. This situation is likely to be aggravated by other modern environmental changes that also tend
to increase inflammatory responses, such as obesity, vitamin D deficiency, and pollutants such as dioxins that drive Th17 cells.
which is a contributing factor to the initiation of some cancers
and to the accelerated growth of others (Fig. 1). It might be
very significant that non-steroidal anti-inflammatory agents,
148
such as cycloxygenase-2 (COX-2) inhibitors, reduce both the
risk of developing certain cancers (such as colon and breast
cancer) and the mortality caused by these same cancers (67).
2011 John Wiley & Sons A/S • Immunological Reviews 240/2011
Rook & Dalgleish Æ Infection, immunoregulation, and cancer
This suggestion would be strengthened if there were evidence
that anti-inflammatory cytokines of the types associated with
immunoregulatory pathways were found to be protective.
Effects of IL-10 on cancer
In IL-10) ⁄ ) mice, severe inflammation occurs in the gut as
soon as colonization with normal microbiota occurs. This
inflammation is mediated by CD4+ Th1-like cells and activated macrophages and is attenuated by administering antiIFN-c antibody. Eventually, the inflammatory lesions resemble
early adenocarcinomas. Restoration of IL-10 is protective:
IL-10) ⁄ ) mice treated with exogenous IL-10 daily from 3 weeks
of age remained free of disease. Similarly, administration of
IL-10 prevented the colitis that occurs in 100% of SCID mice
transplanted with CD45RBhi CD4+ effector T cells. Interestingly, administration of IL-10 to adult IL-10) ⁄ ) mice after the
colitis was established did not cure the colitis but it still very
significantly reduced the incidence of adenocarcinomas (68).
These results imply that in addition to the anti-inflammatory effect, IL-10 is also involved in other protective antitumor mechanisms, and further studies do indeed confirm
this finding. First, there is strong evidence that IL-10 encourages NK cell-mediated tumor cell killing by downregulating
MHC class I, modulating NK cells, and inhibiting angiogenesis
(69–72). It has also been reported that systemic administration of IL-10 induced an effective specific immune response
against established tumors in mice. IL-10-treated mice were
immune to subsequent rechallenge with 10-fold larger numbers of the same but not a different tumor (73). This work in
mice with laboratory tumor cell lines might be too artificial
for extrapolation to humans, but it does imply that IL-10
encouraged an adaptive immune response. In conclusion, it is
not surprising that the presence of high levels of IL-10 in the
serum or within the tumor can be a favorable prognostic indicator for some tumors but an unfavorable one for others (72).
Effects of TGF-b on cancer
The effects of TGF-b on cancer remain controversial. Many
tumors secrete TGF-b, a potent suppressor of the cytotoxic
T-cell response, a crucial anti-tumor effector mechanism,
thereby promoting tumor growth (74, 75). In addition, there
is evidence to suggest that Tregs inhibit the anti-tumor functions of NK cells by expressing membrane-bound TGF-b
(76). Moreover, TGF-bs are involved in epithelial to mesenchymal transdifferentiation. The switch of carcinoma cells to
an invasive phenotype has some similarities to this normal
process, and TGF-b can induce epithelial to mesenchymal
2011 John Wiley & Sons A/S • Immunological Reviews 240/2011
transition in vitro in numerous types of cancer cells (77). Similarly, control of angiogenesis is a normal function of TGF-b,
partly via induction of VEGF, which explains why knockout of
the genes encoding TGF-b1 or TGFbRII is lethal to embryos.
It is therefore not surprising that neutralizing antibodies to
TGF-b can reduce angiogenesis in tumors (77). Hence, there
are several ways in which TGF-b might promote the growth
of established tumors.
TGF-b may, however, have a different role in tumor initiation. The broad anti-inflammatory effects of TGF-b might be
expected to counter inflammation-induced oncogenesis
described earlier. Similarly, TGF-b is a potent inhibitor of
growth of epithelial cells and plays a role in the homoeostasis
of healthy epithelial surfaces (77). Indeed mutations in
human TGFBR2 and in SMAD2 and SMAD4, which are
involved in transduction of signals from the activated TGF-b
receptors, have been found in both sporadic and inherited
colon cancer. Experiments in TGF-b) ⁄ ) mice cast some light
on the mechanism. Germ-free TGF-b) ⁄ )RAG2) ⁄ ) mice do
not develop colitis or cancer. However, when exposed to H.
hepaticus, both colitis and cancer were observed (78, 79). Interestingly, RAG2) ⁄ ) mice, which retain the ability to secrete
TGF-b, remain cancer-free even in the presence of H. hepaticus,
indicating that TGF-b can block oncogenic effects of the
H. hepaticus-induced inflammation.
In conclusion, the available data are compatible with the
view that TGF-b may protect against the initiation of cancer
via its effects on cellular homeostasis and its anti-inflammatory roles. In contrast, TGF-b might promote growth of
tumors once these are established.
Effects of Tregs on cancer
There have been numerous reviews of the detrimental role of
Tregs in progressive established cancer (75), and other
reviews of the ways in which cancer therapy might be
improved by drugs that oppose the functions or development
of Tregs (80). However, since regulatory cytokines can be
shown to have protective effects against the induction of cancers and, in the case of IL-10, some protective effects even
after the tumor has formed, we should expect to find evidence
that Tregs can protect against oncogenesis, perhaps particularly in relation to cancers that are known to be associated
with uncontrolled chronic inflammation (Fig. 5).
Beneficial role for Tregs in animal models of cancer
An example of the protection from oncogenesis by Tregs was
seen in C57BL ⁄ 6 mice infected with Helicobacter felis. This
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Rook & Dalgleish Æ Infection, immunoregulation, and cancer
Beneficial roles of Treg
Treg block oncogenesis in site of
chronic inflammation.
Treg in tumour bed reduce
inflammation, and so block release
of growth and angiogenic factors.
IL-10: Anti-inflammatory
Increase NK activity
Inhibit angiogenesis
TGF-β
β: Anti-inflammatory
Inhibit epithelial growth
Treg from animals that have
experienced infection
Detrimental roles of Treg
Treg in tumour stroma or local
lymphoid aggregates block
development of protective cytotoxic
lymphocyte (CTL) response.
IL-10: Inhibit protective anti-tumour
response
TGF-β
β: Inhibit CTL
Treg from ‘hygienic’ animals
Fig. 5. The heterogeneous roles of Tregs and anti-inflammatory cytokines in cancer. It is well documented that Tregs can oppose protective
responses to cancer. It is now emerging that Tregs of certain poorly defined phenotypes, in certain locations, can be protective against both initiation
and progression of cancer. Tregs can terminate chronic inflammation and so stop oncogenesis. In existing tumors, Tregs can block release of growth
and angiogenic factors, but to achieve this, they need to be in the tumor bed itself. Tregs located in surrounding lymphoid aggregates are more likely
to inhibit generation of the protective T-cell response. We still know little about the control of the localization or phenotype of these Tregs, but in animal models (see Fig. 6), Tregs from infected animals can have the relevant properties, whereas Treg from very clean specific-pathogen free (SPF) animals do not.
organism induces Th1- and IFN-c-dependent gastric atrophy,
a premalignant lesion reminiscent of that which can occur in
humans infected with H. pylori. However, when H. felisinfected mice were co-infected with Heligmosomoides polygyrus, a
natural murine nematode parasite with a strictly enteric life
cycle, there was minimal gastritis, and the premalignant atrophic lesions were not seen (81). The co-infection did not
eliminate inflammation. Indeed, 16 weeks after infection gastric colonization with H. felis was greater in the group coinfected with H. polygyrus, particularly in the antrum, with
extension into the corpus mucosa. However, the inflammation in the co-infected mice was quite different, with
strikingly reduced IFN-c and increased expression of IL-10,
TGF-b, and some Th2 cytokines (81). A similar effect was
revealed using Helicobacter hepaticus, another natural enteric bacterial pathogen of mice. 129 ⁄ SvEv RAG-2-deficient mice were
infected with H. hepaticus by gastric gavage. Many of these animals develop IBD and colon cancer. However, when the
H. hepaticus-infected mice were treated at 1, 3, or 12 months
after infection with adoptive transfer of CD4+CD45RBloCD25+
regulatory cells, they had reduced severity of IBD and
significantly lower risk of colon cancer (82), but only if the
Tregs came from IL-10-competent donors. When Tregs from
IL-10) ⁄ ) mice were used, there was an increased incidence
of mucinous tumors (82). Thus, these models show that
induction of Tregs by co-infection with a helminth (a mechanism discussed above in relation to the Hygiene hypothesis)
or passive transfer of Tregs can convert an inflammatory
150
response from a pattern that causes cancer to one that does
not.
The same group also investigated the APCMin ⁄ + mouse. APC
(adenomatosis polyposis coli) is a human gene that causes
colorectal cancer when it is mutated. APCMin mice have a
point mutation in the murine homologue, and they develop
multiple intestinal adenomas and mammary tumors. However, the number of epithelial adenomas is reduced when heterozygote APCMin ⁄ + mice are treated with CD4+CD25+ Tregs,
but as in the H. felis model discussed above, only if the Tregs
come from IL-10-competent donors (83).
Further work has confirmed the requirement for IL-10
but also revealed that not all Tregs have the same ability to
inhibit oncogenesis (Fig. 6). Tregs transferred from donors
that had been preinfected with H. hepaticus protected against
development of cancer in several models (23). The models
were: (i) colorectal cancer (CRC) developing from inflammatory bowel disease in H. hepaticus-infected RAG2) ⁄ )
129 ⁄ SvEv mice; (ii) CRC and mammary adenocarcinoma in
H. hepaticus-free APCMin ⁄ + mice given pro-inflammatory
effector T cells; and (iii) spontaneous mammary adenocarcinoma in FBV Her2 ⁄ Neu mice. In each case, even when
no Helicobacter was present in the recipient (i.e. the cancer
was spontaneous, or triggered by transfer of pro-inflammatory T cells), only Tregs from Helicobacter-experienced mice
were protective (Fig. 6). When derived from H. hepaticusnaive ‘hygienic’ animals, they exacerbated the cancer in the
first two models and had no effect in the third one. The
2011 John Wiley & Sons A/S • Immunological Reviews 240/2011
Rook & Dalgleish Æ Infection, immunoregulation, and cancer
Treg-deficient effector T
cells (CD4+CD45RBhi)
Mammary
adenocarcinoma
C57Bl APCmin+/–
129 Rag2–/–
Infect with Helicobacter
hepaticus
Transfer of Treg
from infected mice
is protective
Colorectal cancer
Fig. 6. Examples of beneficial effects of Tregs in animal models of
cancer. Transfer of Tregs from animals infected with Helicobacter hepaticus
into animals developing the cancers was protective, even when this organism was not involved in the cancer concerned and was not present in the
recipient. By contrast, Tregs from specific pathogen-free animals were not
protective, indicating that the precise phenotype of the Treg is crucial.
exacerbation might have been due to inadequate release of
IL-10, to conversion to Th17, or to a change in homing.
This implies a functional difference in the Tregs, independent of their specificity.
In conclusion, this series of experiments has shown that a
gut-associated organism (H. hepaticus) can induce and modulate
Tregs in ways that endow them with the ability to control cancer-promoting inflammation throughout the body (i.e. in the
breast as well as the gut) via an IL-10-dependent mechanism.
This constitutes experimental evidence for the relevance of the
Hygiene hypothesis to cancer.
Location and function of Tregs in cancer
The strategies that are effectively anti-tumor in the models
discussed in the previous section also caused a change in the
location of Foxp3+ Treg cells. Tumor progression was associated with Foxp3+ cells in lymph nodes and in tissue surrounding the tumor, whereas remission was associated with Foxp3+
cells in the tumor itself (23). Female FVB strain MMTV-HER2 ⁄ neu (ErbB2) transgenic mice have a genetically determined
tendency to develop mammary tumors resembling those seen
in 30% of humans with breast cancer. Growth of the tumors
requires ongoing inflammation. Working with mice already
bearing tumors, it was found that administration of anti-TNF
significantly decreased subsequent tumor growth. Interestingly, the anti-TNF also caused accumulation of Foxp3+ cells
in the tumor itself, whereas in untreated animals with more
rapidly progressing tumors, there were no Foxp3+ cells in the
tumor but instead an accumulation in the lymph nodes and
tissue surrounding the tumor. These authors observed a similar phenomenon in the APCMin ⁄ + mouse model (23).
2011 John Wiley & Sons A/S • Immunological Reviews 240/2011
This observation might be relevant to human disease. The
assessment of numbers of circulating Tregs or of Tregs infiltrating the tumor itself has been used as a prognostic indicator
in human cancers, though the correlations found depend on
the tumor studied. Their presence has been claimed to be a
negative prognostic indicator in carcinomas of the lung, pancreas, stomach, liver, and ovary, whereas Tregs appeared beneficial in B-cell lymphoma, head and neck, and colon
carcinoma, though in other studies numbers of Tregs have not
correlated with changes in survival (reviewed in 84). This heterogeneity of results suggests that something is being missed,
and the animal models discussed above suggest that the localization of the Tregs might be crucial. A study that counted
infiltrating Tregs in breast cancer concluded that high numbers of these cells were detrimental to survival (85), but a further study that recorded the precise location of the Tregs
concluded that the presence of Foxp3+ Tregs within the tumor
bed did not affect the patients’ clinical evolution, whereas
their presence in lymphoid-enriched areas correlated with a
higher risk of relapse, a shorter relapse-free survival, and
reduced overall survival (84). This finding agrees with the
animal models described above (23) and might suggest that
Tregs in the lymphoid aggregates can inhibit the development
of effector cells such as CTLs, whereas Tregs in the tumor bed
can usefully inhibit the tumor-promoting effects of inflammation discussed earlier.
The microanatomical location is also crucial when considering the role of tumor-infiltrating macrophages. These correlate with improved survival if present in the tumor ‘islets’,
among the tumor cells, but are linked to a poor prognosis if
present in the surrounding stromal tissue (86). It is possible
that stromal macrophages support tumor growth by enhancing formation of tumor stroma and angiogenesis, whereas
macrophages in contact with tumor cells are cytotoxic, and so
limit tumor growth.
As a further example, in a murine model of colon adenomatous polyposis, there is focal mastocytosis that promotes
tumor initiation and progression (87, 88). Adoptively transferred Tregs suppress this mastocytosis. In contrast, the
endogenous Tregs that are present in the polyps in large numbers show proinflammatory activity and promote differentiation and expansion of mast cells (87, 88). It is known that
Tregs can be incapacitated by exposure to TNF (89) or IL-6
(90), so it may be that when Tregs fail to suppress inflammation, perhaps because TNF and IL-6 are being released spontaneously from the tumor cells (and in this model, by the mast
cells) their function can be perverted. Indeed, Treg cells that
expand in adenomatous polyps no longer produce IL-10 and
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Rook & Dalgleish Æ Infection, immunoregulation, and cancer
instead switch to production of the pro-inflammatory
cytokine IL-17 (87).
Treg modulation of inappropriate inflammatory
mechanisms in cancer
Tregs not only inhibit inflammatory responses but also influence the balance between different effector cell types and
selectively alter cytokine secretion profiles. For instance,
Foxp3+ Tregs can functionally differentiate to acquire an ability to specifically control Th1 or Th2 type immune responses
by modifying their expression of Th1-related or Th2-related
transcription factors (91). Thus, some natural Foxp3+ Tregs
express T-bet, which increases when they are stimulated in a
Th1 cytokine environment. This causes upregulation of C–X–
C chemokine receptor 3 and promotes recruitment to sites of
type 1 inflammation. Foxp3 also controls expression of the
transcription factor IFN regulatory factor 4 (IRF4), which is
required for Th2 differentiation. Deletion of IRF4 from Tregs
impairs their ability to control Th2- but not Th1-mediated
inflammation (92). Therefore not only is the location of the
Treg crucial but also their precise function. They need to be
able to inhibit the types of T cell that are detrimental to tumor
immunity such as Th2 cells. The inflammatory cells that infiltrate tumors are often not well adapted to the role of driving
Th1- and CTL-mediated anti-tumor responses and show a Th2
bias. The dendritic cells tend to have an immature phenotype,
and the myelomonocytic cells express the alternative M2 phenotype (19). M2 macrophages are driven by signals such as
IL-4, IL-13, glucocorticoids, and IL-10. They express low
IL-12 but high IL-10, IL-1decoyR, IL-1ra, and scavenger
receptors (SR-A and mannose receptors). These cells promote
Th2 responses, scavenge debris, and drive angiogenesis and
tissue remodeling as discussed earlier (18).
Thus although there is strong evidence that Th1-mediated
inflammation has a particular tendency to initiate oncogenesis
(68), once a tumor is established, a switch to a Th2 pattern
may reduce anti-tumor mechanisms, while the Th2-associated
repair and angiogenic functions facilitate growth (18, 19). In
this context, it is interesting that several of the organisms
involved in the Hygiene hypothesis have the ability to drive
Tregs that can suppress Th2 responses. This includes M. vaccae
(93), various helminths (94–96), and H. pylori (discussed in
detail below).
Epidemiology of cancer in relation to infection
An examination of the epidemiology of some of the cancers
that increase markedly in incidence as developing countries
152
adopt the lifestyle of rich industrialized countries reveals
trends that mimic those that led to the invocation of the
Hygiene hypothesis to explain the rising incidence of chronic
inflammatory disorders. For instance, age-specific incidence
rates for specific cancers in Asians correlate with the state of
economic development of their country of residence. Incidences are much lower in Asians living in India compared to
those living in the UK or USA (97).
Hodgkin’s lymphoma
The risk of classical Hodgkin’s lymphoma (HL) is inversely
associated with socioeconomic status (98). In the West, HL is
most prevalent among whites, followed by blacks and Hispanics, with the lowest incidence in Asians. Nevertheless,
although incidence is low in Asian subgroups (presumably for
genetic reasons), rates in Asians residing in the US are almost
double the rates in Asians living in Asia, so there are clearly
environmental factors that partly compensate for this resistance when Asians move to the USA (99). Early exposure to
other children at nursery school and day care seems to
decrease the risk of HL in young adults, and the risk is lowest
among those with multiple older but not younger siblings.
Having older siblings is associated with earlier exposure to
common childhood pathogens and Old Friends (100), and
this is precisely the observation that, in relation to allergies,
led to the Hygiene hypothesis (101). We know that delayed
exposure to some infections that are usually harmless in neonates can result in serious disease (e.g. polio or hepatitis A
virus) and delayed exposure to viruses has also been considered by some authors in relation to the rise in Type 1 diabetes
(102). There is evidence that HL is associated with EBV,
which appears to increase the risk fourfold. Clearly the vast
majority of individuals with EBV do not develop HL (100,
103), and this association does not explain the socioeconomic
or family size data.
Acute lymphatic leukemia of childhood
The epidemiology of acute lymphatic leukemia (ALL) of
childhood also shows striking parallels with the epidemiological findings that gave rise to the original version of the
Hygiene hypothesis (101, 104). A study in Northern California provided preliminary evidence that protection from ALL
is proportional to the number and frequency of social
contacts (105). A large population-based case–control study
[The UK Childhood Cancer Study (UKCCS)] revealed further
evidence that social contacts in infancy can reduce risk of
childhood ALL (106). Interestingly, early playgroup
2011 John Wiley & Sons A/S • Immunological Reviews 240/2011
Rook & Dalgleish Æ Infection, immunoregulation, and cancer
Normal (ancient)
Mid 19th–early 20th C
Loss of helminths ------------>
Gastric atrophy
- B12 deficiency
- Iron deficiency
- Some adenocarcinoma in old age
Late 20th C
--- Loss of H. pylori (antibiotics) --->
Peptic ulcer disease
shows sharp peak
Sustained high acid,
oesophageal
adenocarcinoma
Progressive loss of Treg, more allergic disorders
Fig. 7. The changing role of Helicobacter pylori. Human studies and animal models suggest that in the presence of co-infection with Treg-inducing
helminths, the inflammatory response induced by H. pylori is attenuated but involves the whole stomach. Adenocarcinoma is a late consequence in
some individuals. As helminths are progressively eliminated, a more vigorous response occurs, and peptic ulceration is seen in individuals whose Treg
response to H. pylori itself is suboptimal, while H. pylori becomes confined to the pylorus. More recently, the situation has been complicated by the fact
that long-term infection with H. pylori results in decreased acid production. Thus, total loss of H. pylori due to antibiotics results in sustained high levels
of acid production and consequent esophageal adenocarcinoma (modified and redrawn from reference 113).
attendance appeared to give some protection against not only
ALL but also to a limited extent against other pediatric cancers such as central nervous system tumors (106, UKCCS
investigators, unpublished data quoted in 104). Equally striking is the fact that an analysis of data from 40 countries
revealed a very significant positive correlation between incidences of ALL and Type 1 diabetes. Both diseases also correlated positively with GDP (107). A similar analysis had
previously revealed a correlation between Type 1 diabetes
and allergic disorders (108).
Carcinoma of the stomach or esophagus
The story of H. pylori is particularly instructive, because we
know which organism is involved and we have some insight
into the mechanisms. The majority of epidemiologic studies
have reported a decreased incidence of gastric cancer in Africa
compared to other countries where H. pylori infection is endemic. This is often described as ‘The African Enigma’. Looking
at IgG subclasses as an approximate measure of the relative
balance of Th1 and Th2-mediated response it was noted that
the citizens of Soweto (an economically impoverished township near Cape Town, South Africa) had a more Th2-biased
response to H. pylori than did people from Europe or Australia
(discussed in 109). An appealing hypothesis is that the
inflammatory effect of H. pylori in man is modified by simultaneous helminth infections, as demonstrated in experimental
2011 John Wiley & Sons A/S • Immunological Reviews 240/2011
models outlined earlier (23, 81). The milder chronic inflammation or increased immunoregulatory networks seen in the
presence of helminths might mitigate the risk of stomach
cancer (Fig. 7).
Gastric ulcer disease due to H. pylori appeared in the 19th
century in the USA and Europe, and its prevalence peaked in
the early 20th century. Duodenal ulcer disease appeared and
peaked 10–30 years later (110, 111). This again could be due
to changes in immunoregulation; peptic ulcer disease is associated with reduced expression of Foxp3, IL-10, and TGF-b in
gastric biopsies from H. pylori-infected donors (112). The
modern lifestyle may be associated with poorly controlled
Th1-orientated inflammation, causing more acute local damage and also causing the infection to be more frequently confined to the antrum of the stomach, whereas the typical
situation observed in patients in developing countries is a
milder pan-gastritis (113).
Modern hygiene and antibiotics are leading to populations
where many individuals do not carry H. pylori at all. Some
authors believe that this total absence of colonization by
H. pylori may be responsible for recent increases in the incidence of short- and long-segment Barrett’s esophagus and its
malignant complications (114, 115). The reasoning here is
that in the absence of the complex biological effects of H.
pylori, which include mucosal atrophy, acid production by the
stomach is excessive, leading to chronic inflammatory esophagitis and carcinogenesis (Fig. 7).
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Rook & Dalgleish Æ Infection, immunoregulation, and cancer
It is important to note that H. pylori is itself a potent inducer
of Tregs, both locally in the stomach and duodenum (112,
116), and systemically (116), though Tregs are reduced in
patients who develop ulcers (112). The changes in malignant
and non-malignant manifestations of H. pylori described above
have coincided with the striking increases in allergic disorders
that prompted the Hygiene hypothesis. Interestingly, epidemiological studies indicate that infection with H. pylori protects
against allergic disorders (57, 117), and similar effects are
seen in laboratory models (118, 119). Thus H. pylori may provide an interesting example of the parallel between the
hygiene of Old Friends hypothesis as applied to chronic
inflammatory disorders and its application to cancer.
Colon cancer
Worldwide, colorectal cancer incidence rates increase as countries undergo the second epidemiological transition to economic development and remain high in longstanding,
economically developed countries such as Japan, Australia,
Western Europe, and North America (120). Part of this
increase is associated with the increase in inflammatory bowel
disease (IBD), in which the Hygiene hypothesis is already
implicated. As outlined above, helminth infection can reduce
colorectal cancer by inducing anti-inflammatory immunoregulation in a mouse model (81), and helminths have a therapeutic effect in human IBD (121, 122). However, other
components of the microbiota also have important immunoregulatory functions (123). The microbiota can be altered by
inappropriate diet, and obesity is associated with a distinct
pattern of changes in the gut microbiota (124). Similarly,
antibiotics have profound effects on the nature and diversity
of the intestinal microbiota (125). After a severe transient gut
infection, a different stable ecosystem can take over (dysbiosis), which can keep the host alive, but leads to illnesses such
as irritable bowel syndrome and IBD (126), with consequent
susceptibility to inflammation-related cancer.
Hygiene hypothesis, depression, and cancer
Depression provides another important potential link between
the Hygiene hypothesis and cancer. Depression predicts
increased mortality in cancer patients. This is true whether
depression is diagnosed before or after cancer diagnosis and
remains after controlling for confounding medical variables
(127). An analysis of 25 independent studies reported that
mortality rates were up to 25% higher in patients experiencing depressive symptoms (P < 0.001) and up to 39% higher
in patients diagnosed with major or minor depression
154
(P = 0.03) (128). Chronically raised levels of circulating proinflammatory cytokines can lead to depressive symptoms, and
there is a subset of individuals with depression in whom the
mood disorder may be caused by the same failure to terminate
inappropriate inflammatory responses that lies behind the
increases in somatic inflammatory disorders (allergies, IBD,
autoimmunity) frequently discussed in relation to the
Hygiene hypothesis (129, 130). Several anti-inflammatory
agents such as anti-TNF and NSAIDs have now been found to
exert anti-depressant effects (131). Interestingly, in an animal
model heat-killed Mycobacterium vaccae, a potent inducer of Tregs
(93), had anti-depressant effects similar to those of Prozac,
and a subset of serotonergic neurons involved in this effect
was identified (132). We can therefore postulate that by
inducing regulatory mechanisms and reducing circulating
pro-inflammatory cytokines, the microbial exposures involved
in the Hygiene hypothesis may exert a supplementary
anti-cancer effect, secondary to improvements in mood and
coping.
Microorganisms and immunotherapy of cancer
The arguments and data presented above suggest that
microbes or their components could have a role to play in
cancer prevention by exerting immunoregulatory effects that
suppress chronic oncogenic inflammation. Similarly, these
preparations might aid treatment of established cancer by
altering the balance of effector mechanisms, suppressing those
that are unhelpful or detrimental (Th2), and driving effective
anti-tumor effector pathways. In principle it might be possible
to drive subsets of Tregs that block inflammation in the tumor
bed (and so limit vascularization, and the provision of growth
factors), without blocking the generation of effector cells in
the lymphoid tissue (84). This aspect has not yet been investigated.
Many research groups are trying to use microorganisms or
their components as adjuvants and as carriers of tumor target
antigens. The organisms selected are often intracellular infections. Thus, Listeria monocytogenes is being developed as a carrier
of tumor antigens that enters APCs (133, 134), and components of Toxoplasma gondii are being used in a dendritic
cell-based therapeutic cancer vaccine (135). However, most
studies on the use of microorganisms for immunotherapy in
human have used mycobacteria.
Cancer immunotherapy with mycobacteria
The best-established use of immunotherapy is intravesical
BCG for bladder cancer. The mode of action is unclear, but a
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Rook & Dalgleish Æ Infection, immunoregulation, and cancer
recent review of 80 randomized trials and 11 meta-analyses
concluded that intravesical BCG, although more toxic, is more
effective than mitomycin-C for the prophylaxis of tumor
recurrence in high-risk patients, although there is no significant difference in overall survival. Chemotherapy and BCG
seem to be equally effective in preventing recurrence in intermediate risk groups (136). BCG has been tested in many other
cancer types and is still sporadically used in melanoma. An
examination of all reported trials available found a trend to
enhanced survival in patients with stage III malignant melanoma and cutaneous non-visceral metastases given intralesional BCG (137).
More recently, cancer studies have been concentrating on a
different mycobacterium (M. vaccae) that has unusual immunological properties. Used as a heat-killed preparation, it
drives Tregs and inhibits Th2 (93) but encourages cytotoxic
T cells (138) and NK activity (139). Encouraged by several
studies of heat-killed M. vaccae in animal models of various
cancers, by Phase II studies on intradermal M. vaccae in prostate cancer (140), and in inoperable non-small cell lung cancer and mesothelioma (141), an open label Phase III trial
was performed in a total of 419 patients with several types
of lung cancer, mostly squamous cell carcinoma and adenocarcinoma (142). Deficiencies in the study design led to poor
compliance, with only 53% receiving more than two injections of M. vaccae, and the analysis plan did not allow for
independent appraisal of the different cancer types. Overall
there was no survival advantage in the group receiving
M. vaccae, but patients showed significantly less deterioration
in their Global Health Status score (P = 0.02), particularly
those parameters related to mood, coping, and depression
(see previous section). Meanwhile, a separate analysis of
compliant patients confirmed that while treatment with M.
vaccae gave no survival benefit in squamous cell carcinoma, in
sharp contrast, survival of compliant adenocarcinoma patients
receiving M. vaccae was increased by a mean of 135 days
(P = 0.0009, Kaplan–Meier log rank test) (143). This analysis fell outside the original analysis plan of the Phase III trial
and must therefore be treated with caution, but it has been
sufficient to motivate further trials that are now being
planned.
Heat-killed M. vaccae was also tested as an immunotherapeutic agent for patients with metastatic, postnephrectomy, renal
cell carcinoma. Sixty patients received injections of M. vaccae
intradermally on entry and after 2, 4, 8, 12, 16, 20, and
24 weeks. Subsequently, they received injections every
8 weeks. Survival was compared with that of historical con-
2011 John Wiley & Sons A/S • Immunological Reviews 240/2011
trols who had been treated either with biological response
modifiers (IL-2, IFN-a) or with chemotherapy. Those treated
with M. vaccae alone survived as long as those receiving IL-2 or
IFN-a, and both treatment groups survived longer than those
on chemotherapy (P < 0.001) (144). In a second small study,
36 patients were randomized to receive treatment with IL-2
alone or IL-2 plus M. vaccae. Those receiving IL-2 alone had significantly more adverse events than those receiving M. vaccae
plus IL-2 (P < 0.001) (144). This combination therapy was
prompted by a previous pilot study suggesting that the combination of M. vaccae and IL-2 might be more beneficial than
M. vaccae alone in melanoma (145). A small biotech startup
(Immodulon; http://www.immodulon.com/index.php) is
currently setting up trials of cancer immunotherapy using a
very similar organism.
Conclusions
In this review, we have brought together information from
several different disciplines. Until now, the thinking that has
been applied to the increases in chronic inflammatory disorders in rich developed countries has been entirely different
from the thinking applied to similar increases in many cancers, despite rather precise epidemiological parallels. Here we
have discussed the ability of infections to cause cancer but
also pointed out that the immunodysregulation that accompanies the Western lifestyle might also contribute both to
oncogenesis and to subsequent inability to control or eliminate incipient cancers. A greater understanding of these interactions might pave the way to improved microbe-based
immunotherapies. Interestingly, the intracellular infections
are central to this analysis and particularly to therapeutic
studies currently in progress, and these results may provide
valuable new tools.
An obvious limitation of this discussion is the fact that most
of the evidence that Treg and anti-inflammatory cytokines can
sometimes protect against development or progression of
cancer comes from animal models. We cannot yet state with
certainty that the same is true for any human cancers. Nevertheless, the situation is changing, and as attention is focused
more precisely on the exact location and phenotype of the
Treg in human disease, the heterogeneity is beginning to
emerge, and evidence of protective roles in some cancers is
becoming suggestive. We hope that this review will encourage further explorations of this area which has the potential to
influence both the prevention and treatment of those cancers
for which it proves relevant.
155
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