Download The clinical implications of antitumor immunity in head and neck

The Laryngoscope
C 2011 The American Laryngological,
V
Rhinological and Otological Society, Inc.
Contemporary Review
The Clinical Implications of Antitumor Immunity in Head and Neck
Cancer
Clint T. Allen, MD; Nancy P. Judd, MD; Jack D. Bui, MD, PhD; Ravindra Uppaluri, MD, PhD
Recent developments have renewed interest in understanding the interaction between transformed cells and
the immune system in the tumor microenvironment. Here, we provide a comprehensive review addressing the basics
of tumor immunology in relation to head and neck cancer and the cellular components potentially involved in antitumor immune responses. In addition, we describe the mechanisms by which head and neck cancer cells escape
immune-mediated killing and progress to form clinically significant disease. Further, we detail what effects standard
anticancer therapies may have on antitumor immune responses and how these responses may be altered by current
and investigational immunotherapies. Finally, we discuss future directions that need to be considered in the development of new immunotherapeutics designed to durably alter the immune response in favor of the host.
Key Words: Tumor immunity, head and neck cancer, standard therapy, immunotherapy.
Laryngoscope, 122:144–157, 2012
INTRODUCTION
Despite advances in our understanding of the dysregulated pro-growth and pro-survival intracellular
signaling pathways that lead to the development of head
and neck squamous cell carcinoma (HNSCC), meaningful changes in therapeutic outcomes utilizing this
knowledge in patients has not been achieved. Excluding
human papilloma virus (HPV)-associated oropharyngeal
cancer, locoregional control of disease and corresponding
survival rates for carcinogen-associated HNSCC remains
poor with less than half of patients presenting with
advanced disease alive 3 years after therapy.1
In recent years, an improved understanding of the
role of the immune system in both preventing formation
and modulating progression of mouse and human malignancies has refocused interest in using the immune
system to eliminate cancer. Physicians and scientists
understood the theoretical potential of the immune system to recognize and eradicate malignant disease almost
a century ago, in part based on the seminal work of surgeon William Coley,2 but the lack of modifiable murine
From the Department of Otolaryngology—Head and Neck Surgery
(C.T.A., N.P.J., R.U.), Washington University School of Medicine, St. Louis,
Missouri, U.S.A.; and Department of Pathology (J.D.B.), University of
California at San Diego School of Medicine, San Diego, California, U.S.A.
Editor’s Note: This Manuscript was accepted for publication May
5, 2011.
The authors have no financial disclosures for this article.
The authors have no conflicts of interests to declare.
Send correspondence to Ravindra Uppaluri, Washington University School of Medicine, Department of Otolaryngology, Box 8115, 660
South Euclid Avenue, St. Louis, MO 63110. E-mail: [email protected]
DOI: 10.1002/lary.21913
Laryngoscope 122: January 2012
144
models available to dissect the cellular and molecular
basis for an antitumor immune response prevented progression of the field.3 Recent advances have allowed for
investigation of the principles governing the highly complex processes involved in tumor–host cell interactions
occurring within the tumor microenvironment.4
Coupled with this knowledge and the inadequacies
of current carcinogen-associated HNSCC therapeutics,
investigation into the role of the immune system in
HNSCC has resulted in a rapid expansion of knowledge
regarding how the host immune system interacts with
HNSCC tumor cells. This review is intended to educate
physicians and surgeons who care for patients with
HNSCC on the basics of immune function as it relates to
tumor immunology, mechanisms of immune escape by
HNSCC, and how current and investigational therapies
have the potential to modulate these antitumor immune
responses.
DISCUSSION
Evidence Implicating Immune Function as a
Barrier to Tumorigenesis
All cells in the human body have multiple lines of
defense against cellular transformation. Intrinsic protein
signaling cascades induce programmed cell death in the
presence of DNA damage, cellular stress, or uncontrolled
cell growth.5–7 Cells that escape these regulatory barriers must then avoid anoikis and develop the ability to
grow and divide away from their basement membrane
attachments.8 Although intrinsic pathways of tumor
suppression clearly operate to limit the development of
Allen et al.: Immunobiology Head and Neck Cancer
malignancy, the immune system, a potentially ‘‘extrinsic’’
tumor suppressor system, also inhibits tumor formation.
This role for the immune system may extend from its
ability to efficiently protect our tissues from pathogens
by responding to danger signals emitted from cells under
stress.9
The most direct evidence for the role of the immune
system in modulation of tumor development comes from
studies in mice. Before the development of inbred lines
of mice, investigations into immune response to transplanted tumors could not be differentiated from simple
allograft rejection.3 However, with the availability of
syngeneic mouse models and recombinant technology to
eliminate one or more components of the natural
immune response, antitumor immune responses can now
be observed and documented. In a model of 30 -methylcholanthrene (MCA) carcinogen-induced tumors, mice
deficient in interferon-c (IFN-c) signaling were found to
be substantially more susceptible to tumor formation
than their wild-type counterparts.10 Mice of variable
genetic backgrounds lacking IFN-c were also found to
develop hematologic and epithelial malignancies.11 Mice
deficient for the RAG-1 or RAG-2 proteins (RAG/)
with no functional B- or T-lymphocytes were found to be
significantly more susceptible to both carcinogen-induced
and spontaneously arising tumors,12 implicating lymphocytes as necessary components of the antitumor immune
response. Interestingly, in subsequent experiments
where immunogenicity was addressed by transplantation into syngeneic hosts, tumor cell lines that were
derived from RAG/ mice were highly immunogenic
and more efficiently rejected in wild-type hosts compared
to tumor cell lines derived from wild-type immunocompetent mice.10 The conclusion from these experiments
was that highly immunogenic tumors were eliminated
and weakly immunogenic tumors were selected for by
the intact immune system of the wild-type mice.10,13
Similar findings of decreased tumor latency and
increased tumor formation were observed in a 7,12-dimethylbenz(a)anthracene (DMBA) model of tumor
formation in nude mice with defective T-lymphocyte activity.14 Since these original studies, many reports have
detailed the elaborate mechanisms by which cytokines
and cellular components of adaptive immunity may
mediate tumor elimination, equilibrium and eventual
escape as part of the ‘‘immunoediting’’ hypothesis.10,15,16
Evidence implicating the role of the natural
immune system in protection from tumor development
in humans comes from studying populations of immunocompromised patients. Following immunosuppression
after therapy for solid organ transplantation, multiple
studies have demonstrated increased incidence of de
novo and carcinogen-associated malignancies such as
oral cavity, lung, colon, pancreas, endocrine, kidney, and
melanoma.17,18 Similarly, increased incidence of EpsteinBarr virus, human herpes virus-8, and human papilloma
virus-associated malignancies have been demonstrated
in populations of patients immunosuppressed by HIV or
therapy after organ transplantation as well.19–22 Yet,
these findings may be more related to the inability of an
immunocompromised host to clear a chronic viral infecLaryngoscope 122: January 2012
tion that eventually induces cellular transformation
rather than the immune system’s inability to protect
against the development of a de novo malignancy.
Further data supporting the presence of antitumor
immunity in HNSCC comes from studies correlating the
presence of immune cellularity in tumors with patient
outcomes. Several studies have demonstrated improved
survival or improved local tumor control in tumors with
increased lymphocytic infiltrate.23–25 Extracapsular
spread from lymph nodes, a significant predictor of poor
prognosis in HNSCC, is decreased when primary tumors
have a predominantly CD8þ T-lymphocyte infiltrate.26
Similarly, patients with higher CD8þ T-lymphocyte infiltrate in cervical lymph node metastatic tumor deposits
also have improved outcomes.27 Accordingly, decreased
expression of major histocompatibility molecules (MHC)
class I components critical for antigen presentation is
correlated with poor survival in HNSCC.28,29 Most dramatically, use of microarrays to evaluate gene
expression profiles in patients with HNSCC have demonstrated improved survival in patients with robust
adaptive, but not innate, immune responses.30
The above clinical data suggest a role for the
immune system in modulating the development and progression of human malignancies, such that evasion of
the host antitumor immune response is now included as
one of the ‘‘next generation’’ of hallmarks of cancer.31 To
review the complex mechanisms by which HNSCC cells
in particular have developed to evade the immune system, we first review the relevant functions of the
immune system and how this relates to antitumor
immunity.
Innate and Adaptive Immune Cells in
Antipathogen and Antitumor Responses
The human immune system is classically divided
into innate and adaptive arms. The innate immune
response is nonspecific but has a rapid onset in response
to pathogens, with recognition of invading organisms via
fixed pattern recognition receptors present on the surface of innate immune cells.32 Pro-inflammatory cells of
innate immunity, including dendritic cells (DCs), macrophages (M/s), and natural killer cells (NKs) may exhibit
cytotoxic activity against pathogens themselves but also
serve in roles critical to the priming of the adaptive
immune response. The adaptive response mediated by
B- and T-lymphocytes is slower, due to the need for priming, but ultimately generates a highly specific
cytotoxic response that is durable and results in
memory.12
Immune response to pathogen. Cells of innate
immunity recognize pathogen associated molecular patterns (PAMPs), such as lipopolysaccharide on Gramnegative bacteria and viral nucleic acid, via pattern recognition receptors (PRRs). Direct cytotoxic responses can
occur after cell-to-cell contact or after pathogen recognition and phagocytosis. Digested pathogenic products are
processed into antigenic motifs and presented to cells of
adaptive immunity via MHC class II molecules. Nearly
all nucleated cells in the human body express MHC class
Allen et al.: Immunobiology Head and Neck Cancer
145
I molecules, which serve to continuously sample intracellular proteins endogenous to an individual cell,33,34 but
only certain immune cells express MHC class II molecules. Macrophages and DCs express both MHC class I
and II molecules and as such are termed professional
antigen presenting cells (APCs). The APC function of
M/s and DCs may be compartmentalized, as DCs are
present in the mucosa of the upper aerodigestive tract
(UEDT) and serve to sample this microenvironment for
antigenic stimuli,32 and M/s are commonly found in
other solid organs. A third type of innate immune cell
relevant to antitumor immunity is the NK cell, which
can exhibit direct or indirect cytotoxic activity against
cells with decreased MHC class I expression (the ‘‘missing self ’’ hypothesis)35 or in the presence of other NK
cell receptor ligands.36
The interaction between APCs and T-lymphocytes
to generate a specific cytotoxic response is complex. Antigenic material from the intracellular space presented
via MHC class I molecules is recognized by the T-cell
receptor (TCR) of a CD8þ T-lymphocyte in an MHC-restricted fashion,33,34 and efficient signaling requires
costimulatory signaling via receptor associated molecules
such as B7 on the APC and CD28 on the T-lymphocyte.37
Conversely, antigenic material from the extracellular
space presented via MHC class II molecules on APCs
are recognized by the TCR of a CD4þ T-lymphocyte in a
similar costimulatory molecule-dependent and MHC-restricted fashion.38,39 As undifferentiated CD4þ Tlymphocytes encounter MHC class II:antigen complexes,
the cytokine milieu present in the local microenvironment dictates the activated CD4þ T-lymphocyte’s effector
function.40 In response to bacterial and viral infections,
APCs release interleukin-12 (IL-12), which stimulates
undifferentiated CD4þ T-lymphocytes to become type I
T-helper cells (Th1) cells and secrete IFN-c, tumor necrosis factor-a (TNF-a), and IL-2.41–43 When antigen-specific
CD8þ T-lymphocytes bind MHC class I:antigen complexes in the presence of a Th1 cytokine profile,
cytotoxic T-lymphocytes (CTLs) are generated, which
serve as major mediators of a cytotoxic immune response
via perforin, granzyme, and Fas ligand-mediated apoptosis.44,45 IFN-c also induces expression of MHC class I on
target cells, functionally increasing their antigenicity.46
Alternatively, in response to allergic stimuli and parasitic infections, local microenvironments rich in IL-4
promote CD4þ T-lymphocyte differentiation into Th2
cells which express IL-4, IL-10, and IL-13, generate Blymphocyte-mediated humoral immune responses, and
inhibit CTL activity.47,48 These principles governing
innate and adaptive immune response to pathogens
serve as a framework for understanding immune
responses to tumors.
Immune response to tumor. Due to their physical
location as APCs, DC activation is believed to be a crucial initial step in initiating immune responses against
tumors of the upper aerodigestive tract.49,50 Although
tumor cells do not express PAMPs found on the surface
of pathogens, evidence suggests that cells under distress
may also express damage associated molecular patterns
(DAMPs), such as NK cell receptor ligands, heat-shock
Laryngoscope 122: January 2012
146
proteins, or DNA-associated proteins that may act as the
initial stimuli of an innate immune response.9,51,52 Similar to responses to pathogens, the concept of cytokine
polarization dictating effector cell responses applies to
responses to tumor, with IFN-c expression by Th1 cells
(primed by IL-12 from APCs) allowing generation of
antitumor, antigen-specific CTLs,53 and IL-4, IL-10, and
IL-13 expression by Th2 cells (primed by IL-4 from
APCs)
creating
a
tumor-permissive
environment.12,43,44,54–57 Although much research focus has
been on the development of tumor-specific CTLs themselves, there is increasing recognition of the importance
of crosspriming of T-helper cells to facilitate CTL
development.57
The role of M/s in initiation of immune responses
against mucosal cancers is less clear. Although they
serve as APCs, they are not found in great numbers in
the UEDT mucosal compartment, and they have been
shown to secrete adaptive response-priming cytokines in
response to necrotic but not live or apoptotic cells.58,59
However, in response to activating stimuli such as IFNc, M/s are recruited to and shape the local tumor microenvironment via cytokine expression.60,61 M1 M/s
express IL-12 and TNF-a and promote a Th1 response
and M2 M/s secrete IL-10 and IL-4 and support a Th2
response.60 Although the absolute stimuli that induce
M1 or M2 M/ phenotypes remains unclear, these polarized M/s are drawn into environments where circuits of
autoamplification of either TH1/M1 antitumor or TH2/M2
pro-tumor responses take place.61 Similar populations of
polarized neutrophils have been shown to play a role in
several cancers.62,63
The critical question of how the adaptive host
immune responses distinguish malignant from normal
(self) cells to exert a specific, cytotoxic immune response
was answered by the identification of tumor-associated
antigens (TAAs). Originally identified on the surface of
melanoma cells,64 candidate TAAs may be developmental
or viral proteins, proteins involved in cellular signaling
or metabolism, or products of mutated genes involved in
cellular transformation.13,65–84 Several TAAs capable of
stimulating tumor cell-specific immune responses have
been identified for HNSCC, some of which are cancertestis (CT) antigens normally expressed in adults in
ovarian or testicular tissue only.70,75,78,79,82 Table I summarizes known HNSCC TAAs. Conversely, many
proteins have been shown to be overexpressed either
within or on the cell surface of HNSCC tumor cells, such
as carcinoembryonic antigen (CEA)85 and vascular endothelial growth factor receptor (VEGFR),86 but studies
have failed to date to demonstrate the presence of a natural, in vivo antigen-specific immune response.
Although greatly simplified, a general model to understand the generation of an effective antitumor immune
response would involve a Th1 response primed by
DAMP-activated innate cells to generate CTLs with specific cytotoxic activity against tumor cells bearing TAA.
Other cell types involved in antitumor immunity. Although the TH1/TH2 paradigm provided a
framework for experimental study, further investigation
led to the description of CD4þ T-regulatory and TH17
Allen et al.: Immunobiology Head and Neck Cancer
TABLE I.
Function of Protein
Demonstrated Antigen-Specific
Immune Response
EGFR(853–861)
Signaling protein
Yes (CD8þ CTL response)
Cesson 2010
MAGE-A3
MAGE-A4
Cancer-testis antigens
Yes (CD4þ T-cell response)
Filho 2009
MAGE-3/6
Cancer-testis antigens
Yes (CD8þ CTL response)
Schmitt 2009
RHAMM
G250/CAIX
Hyaluronan receptor
Carbon dioxide metabolism
Yes (CD8þ CTL response)
Ito 2007
Mutated p53
Tumor-suppressor protein
Yes (CD8þ CTL response)
Sakakura 2007
Visus 2007
Wild-type p53
ALDH-1A1
Tumor-suppressor protein
Aldehyde metabolism
Yes (CD8þ CTL response)
Yes (CD8þ CTL response)
Huebeck 2006
KIAA0530
Transcriptional regulation?
Yes (serologic response via SEREX assay)
Rabassa 2006
16 other proteins
MUC-1
Cancer-testis antigens
Mucin protein
Yes (serologic response)
Vaughan 2004
KIAA0530
Transcriptional regulation?
Yes (serologic response via SEREX assay)
Hoffmann 2002
Kao 2001
Wild-type p53
Cyclin-B1
Tumor-suppressor protein
Cell cycle regulation
Yes (CD8þ CTL response)
Yes (CD8þ CTL response)
Mandruzzato 1997
Caspase-8
Apoptosis signaling
Yes (CD8þ CTL response)
HPV-associated HNSCC
Hoffman 2006
HPV-16 E7
Viral oncogene
Yes (CD8þ CTL response)
Albers 2005
HPV-16 E7
Viral oncogene
Yes (CD8þ CTL response)
Reference
Tumor-Associated Antigen
Carcinogen-associated HNSCC
Andrade Filho 2010
ALDH ¼ aldehyde dehydrogenase; CAIX ¼ carbonic anhydrase-IX; CTL ¼ cytotoxic T-lymphocyte HNSCC ¼ head and neck squamous cell carcinoma;HPV ¼ human papilloma virus; MAGE ¼ melanoma antigen gene protein; RHAMM ¼ receptor for hyaluronan-mediated motility; SEREX ¼ serologic analysis of recombinant cDNA expression.
cells. A microenvironment rich in IL-6 and IL-23 drives
undifferentiated CD4þ T-lymphocytes to become TH17
cells that secrete IL-17 and play a role in chronic inflammatory conditions and cellular transformation.87–91
Additional CD4þ T-lymphocytes known to play a major
role in modulating immune responses are T-regulatory
cells (Tregs). Characterized by expression of genes under
the regulatory control of Foxp3, these specialized CD4þ
cells act to suppress immune responses via IL-10 and
TGF-b production and expression of the inhibitory
cosignaling molecule cytotoxic T-lymphocyte antigen 4
(CTLA-4).92–96 Believed to be important for physiologic
immune homeostasis, the immunosuppressive function
of Tregs has been subverted by neoplastic disease to
evade immune elimination92 and the presence of Tregs
has prognostic implications in many types of cancer.97
Other cell types bridge the gap between innate and
adaptive immunity. Gamma-delta T cells (cdT cells) are a
unique subset of T-lymphocytes with a TCR composed of
c and d subunits as opposed to the more common a and b
subunits.98 cdT cells rearrange TCR genes to form an
array of antigen receptors consistent with adaptive immunity, but possess non-HLA-restricted TCRs, respond
quickly without the need for priming and possess phagocytic capability, all qualities consistent with innate
immunity.99,100 cdT cells are present in the epithelium of
the upper aerodigestive tract, and have been shown to
respond to distress signals from epithelial cells.99,101 NK
T cells (NKTs) express surface markers of NK cells but
also express an ab subunit TCR that is not HLA reLaryngoscope 122: January 2012
stricted, but dependent upon a glycoprotein for antigen
presentation.102 NKT function appears to involve perpetuation of an antitumor Th1 or pro-tumor Th2 response
based upon the existing cytokine milieu in the local
microenvironment.103,104
Integration of these data supports the view that
polarization of the cytokine profile in the tumor microenvironment by many different immune cell types
determines the antitumor or protumor responses of
immune effector cells (Fig. 1). Although data suggests
that some of these cell types are initiators of an anti- or
pro-tumor immune response, and that others are only
propagators of that response, the specific contributions
of each cell type in HNSCC remains largely unexplored.
Further studies utilizing relevant models are needed
before we can fully understand the relative importance
of different mechanisms utilized by HNSCC cells to
evade immune detection.
How HNSCC Cells Evade the Immune System in
Immunocompetent Patients
Immune escape is a general term used for the ability of a tumor to avoid immune mediated cell death.
Evidence of a natural tolerance to antigenic stimuli
encountered in the mucosa of the head and neck (the origin of HNSCC) may give HNSCC cells a ‘‘head start’’ in
immune evasion. Further, HNSCC cells possess an arsenal of mechanisms to more directly achieve immune
escape. Hierarchically, these can be organized into tumor
cell evasion of immune detection, direct inhibition of
Allen et al.: Immunobiology Head and Neck Cancer
147
Fig. 1. Diagram of immune cell types that interact with malignant cells in the tumor microinvironment. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
immune cell activity or function, and indirect inhibition
of immune function via recruitment of cells into the
tumor microenvironment with immunomodulatory
function.
Head and neck mucosa may be a tolerant environment. The mucosa of the UEDT is exposed to 500 or
more species of bacteria.105 Yet, the mucosa of the mouth
and pharynx does not exist in a state of perpetual
inflammation. In gut mucosa, antigens are continuously
sampled by DCs and taken to mucosal-associated lymphoid
tissue
(MALT)
where
induction
of
an
immunosuppressive immune response, characterized by
IL-10 and TGF-b expression and Treg activity, allows
the development of tolerance to antigenic stimuli.13,106
This process allows gut-associated microbes necessary
for proper gut function to exist and not be under constant attack by the immune system. Although direct
evidence of tumor-associated antigen tolerance in UEDT
mucosa is still being investigated, evidence that potent
tolerance to UEDT antigenic stimuli mediated by DCs
exists.32,107 and is a mechanism actively utilized by sublingual immunotherapy as a mechanism of inducing
tolerance to environmental and food allergens.108 Further understanding of the role that mucosal immune
tolerance may play in facilitating immune escape of
transformed cells present within the mucosa as well as
which TAAs participate in this tolerance is needed.
Laryngoscope 122: January 2012
148
HNSCC cells evade immune cell recognition
and can directly inhibit immune function. To elicit
an antitumor immune response, immune cells must recognize the transformed cell as dysfunctional. Of the 20,000
or so different proteins expressed in a cell, only a proportion will be abnormal in a transformed cell. Because these
abnormal proteins are generated randomly, and the
mutated peptide needs to possess specific MHC class I
binding motifs, it is unlikely that the tumor cell will present large arrays of antigenic peptides to be recognized by
conventional T cells. In addition, the development of tolerance to self by T-lymphocytes safeguards against
autoimmunity but also poses a great barrier to specific
immune activation against cells endogenous to the
host.109
Cell-to-cell contact between immune and target cells
is critical for immune activation, with MHC class I molecules serving as the scaffold between dysregulated/
mutated intracellular molecules and CTL recognition.
HNSCC cells decrease their inherent antigenicity and
risk of immune recognition by downregulating expression of surface HLA class I molecules.28,29,110 HNSCC
cells also have reduced surface expression of costimulatory B7 molecules, necessary for efficient signaling
through TCRs.111,112 Downregulation of B7 expression in
HNSCC cells is driven at least in part by pro-inflammatory cytokines expressed by the HNSCC cells
themselves, and evidence suggests that B7 expression
Allen et al.: Immunobiology Head and Neck Cancer
can be rescued by IFN-c.113 Interestingly, mutant p53,
detectable in 50% of HNSCC tumor cells, may promote a
pro-tumor Th2 phenotype in a MHC class II-restricted
fashion.114 Further, expression of Fas ligand on HNSCC
cells induces Fas/FasL pathway cell death (apoptosis) in
the IL-2 activated lymphocytes themselves, turning one
of the major mechanisms of T-lymphocyte mediated cell
killing on itself.115 Similarly, HNSCC tumor cells express
PD-L1,116 a B7 family molecule, and galectin-1,117 a
sugar-binding lectin, both of which have been shown to
induce apoptosis of tumor-specific activated CTLs.117,118
A large body of evidence suggests that HNSCC cells
produce factors that induce both local and systemic
immunosuppression. Supernatant from HNSCC cell
lines induces DCs to produce Th2 cytokines with subsequent inhibition of T-lymphocyte function.119 Expression
of VEGF from HNSCC cells inhibits functional maturation of DCs, reducing their antigen presenting
capabilities.120 HNSCC cells directly secrete several
immunosuppressive cytokines, such as IL-10, TGF-b,
and prostaglandin E2 (PGE2),121 which inhibit the local
development of IFN-c secreting T-lymphocytes in vitro
and in vivo.122,123 Granulocyte/monocyte-colony stimulating factor (GM-CSF) has been shown to have conflicting
roles in HNSCC. Produced by stromal cells, T-lymphocytes, and macrophages, GM-CSF promotes recruitment
and expansion of myeloid immune cells and has been
associated with an antitumor Th1 response, but has also
been shown to be produced by HNSCC tumor cells themselves, promoting tumor cell growth and migration and
reduced antigenicity in an autocrine fashion.113,124
Patients with HNSCC have decreased levels of
peripheral circulating NK cells, CD4þ and CD8þ T-lymphocytes and NKT cells.125–127 Further, CTLs present in
the circulation of patients with HNSCC have an apoptotic phenotype,128 suggesting that the T cells that are
present are dysfunctional. Decreased levels of circulating
T-lymphocytes as well as NKT cells have been correlated
to decreased patient survival and local tumor control as
well as tumor recurrence.126,127 Patients with HNSCC
have elevated levels of Th2 cytokines and decreased
levels of Th1 cytokines in circulation compared to normal controls.129,130 These data and others131 suggest
that the HNSCC cell-mediated in vivo immunosuppression is systemic and not just limited to the tumor
microenvironment.
Immunosuppressive immune cells are present
in the HNSCC tumor microenvironment. Immune
cells of both lymphoid and myeloid lineages, with specific roles in normal immune function, are subverted by
tumor cells to generate a microenvironment that promotes tumor initiation and progression. Patients with
HNSCC have elevated levels of Tregs in their
blood92,95,125 as well as recruitment of these cells into
the tumor microenvironment.94,132 Tregs in the HNSCC
microenvironment express Th2 cytokines and the immunosuppressive cytokine TGF-b,94,132,133 and inhibit
antitumor CTL function.133 Treg expression of immunosuppressive cytokines is stimulated at least in part by
HNSCC
cell
COX-2
expression.96
Aside
from
CD4þFoxp3þ Tregs, two groups have demonstrated the
Laryngoscope 122: January 2012
presence of HNSCC cell-induced immunosuppressive Tlymphocytes that may develop from senescent T-lymphocytes in response to the Th2 cytokine IL-10.134,135
Clearly, immunosuppressive T-lymphocytes contribute to
the tumor-permissive HNSCC microenvironment.
Tumor-associated
macrophages
(TAMs)
are
recruited from pools of circulating mononuclear cells to
the HNSCC tumor microenvironment by a number of
potent chemotactic stimuli including monocyte chemotactic protein 1 (MCP-1) and TGF-b secreted from both
tumor cells and other infiltrating immune cells.136,137
TAMs secrete IL-1, IL-8, and both pro-angiogenic and
pro-lymphangiogenic isoforms of VEGF in the tumor
microenvironment.136 These factors induce HNSCC cells
to express more pro-inflammatory and pro-angiogenic
factors, creating a paracrine loop between the infiltrating TAMs and the tumor cells.137 TAMs also secrete IL6, a potent pro-inflammatory cytokine known to induce
STAT3 dependent pro-growth and pro-survival pathways
in HNSCC cells.138,139 Accordingly, serum IL-6 levels in
HNSCC patients correlate strongly with survival and
response to therapy.140,141
Tumor specimens from patients with HNSCC demonstrate robust innate immune cell infiltration.142,143
Recent evidence from several different tumor models
suggests that TAMs present in tumor specimens in general are polarized, M2 M/s,144 although direct evidence
specifically demonstrating the presence of M2 M/s in
HNSCC tumors is lacking. In mice, endogenous IFN-c
promotes the development of M1 M/s via the suppression of M2.145 Consistent with the hypothesis of an
immunosuppressive M/ phenotype in HNSCC, however,
is evidence that increased M/ accumulation in HNSCC
tumors is correlated with an increased tumor cell proliferative rate, advanced primary disease, and increased
rates of cervical metastasis and extracapsular extension.142,143 Similar to polarized TAMs, tumor-associated
neutrophils (TANs) are neutrophils present in the tumor
microenvironment that are functionally polarized into
antitumor N1 or pro-tumor N2 types. The immunosuppressive cytokine TGF-b induces TANs to assume an N2
phenotype, express angiogenic and extracellular matrix
degrading factors, and inhibit CTL responses.146
Although the presence of N2 TANs in HNSCC has yet to
be confirmed, neutrophils and robust TGF-b expression
have been shown to be present in HNSCC specimens.147
Immature immune cells also play a role in immunosuppression within the tumor microenvironment. CD34þ
progenitor cells are a subset of immature cells of myeloid
origin with immunosuppressive properties found in
HNSCC tumors. CD34þ progenitor cells inhibit T-lymphocyte function, and increased numbers in HNSCC
tumors correlate with tumor recurrence and metastasis.148 Factors secreted from HNSCC cells induce CD34þ
progenitor cells to become endothelial cells,149 and these
endothelial cells retain their ability to induce T-lymphocyte dysfunction and promote an immunosuppressive
microenvironment via expression of PGE2.150,151 Similar
populations of immature immunosuppressive cells found
in many solid tumor types, including HNSCC, are myeloid derived suppressor cells (MDSCs).152,153 These
Allen et al.: Immunobiology Head and Neck Cancer
149
immature cells of myeloid lineage are recruited to
tumors from bone marrow via tumor cell production of
chemotactic and pro-inflammatory cytokines such as
GM-CSF, IL-1, and IL-6, where they express the Th2
cytokine IL-10, recruit M2 M/s and Tregs, and induce
T-lymphocyte dysfunction via direct and indirect mechanisms centered around arginine and nitric oxide
metabolism153–155 that can be modulated in part with
pharmacologic therapy.153 In mice, Gr1þCD11bþ MDSCs
demonstrated the ability to either enhance or inhibit
CD8þ CTL activity depending on the presence of Th1 or
Th2 cytokines,156 underscoring the importance of the
background cytokine profile present in the tumor microenvironment. That MDSC accumulation occurs in
response to pro-inflammatory cytokines secreted by tumor and stromal cells alike serves to reinforce the link
between chronic inflammation and cancer.155,157
As detailed above, HNSCC cells have developed
numerous ways to evade immune detection and elimination. That tumor cells would ‘‘spend the energy’’ to
develop such immune-evasion mechanisms speaks to the
natural antitumor role of the immune system itself. In
keeping with the immunoediting hypothesis, HNSCC
cells that survive initial eradication by the immune system to become clinically evident are, by definition,
selected for and possess one or more of these mechanisms of immune escape. Thus, therapeutic intervention
that directly addresses one or more of these immune
escape mechanisms is possible and likely to be more successful than nonspecific approaches.
Effects of Standard HNSCC Treatment on
Immune Function
Although most patients with early (stage I/II)
HNSCC or HPV-associated oropharyngeal SCC are curable and demonstrate good locoregional control, patients
with advanced (stage III/IV) carcinogen-associated
HNSCC in general exhibit poor locoregional control and
high recurrence rates.158 Standard therapies for early
HNSCC include surgery or primary radiotherapy, with
adjuvant radiotherapy in selected cases with specific
clinical or pathologic findings. Chemotherapy, originally
used to treat systemic disease, is now utilized as combination therapy in locoregionally advanced HNSCC with
adverse features or in the setting of distant metastatic
disease.159 Despite numerous prospective trials using
various combinations of surgery, chemotherapy, and
radiotherapy to improve locoregional control, survival
rates for advanced carcinogen-associated HNSCC remain
dismal.160 Accordingly, clinicians and scientists have
begun to search for alternate forms of therapy in
attempts to improve patient outcomes, and many are focusing on modulation of the natural antitumor immune
response as well as potential impacts of standard anticancer therapies on these responses.
The idea that standard anticancer therapy may
result in a detriment to natural host tumor resistance is
not new. As physicians and scientists began to debate
the efficacy of different forms of primary therapy for
cancer, and as further understanding of cancer biology
Laryngoscope 122: January 2012
150
was gained, recognition of the effect that these therapies
may have on the host was articulated:
‘‘Many people are beginning to believe that cancers
are developing continuously in all of us. We have to be
very careful not to destroy the immunologic resistance of
the host. Immunosuppressive therapy with cytotoxic
agents may sharply reduce or completely abrogate any
immunity that a patient may have with cancer. Corticosteroids may have the same effect. By removing
uninvolved regional lymph nodes or subjecting them to
radiation, one may remove the patient’s immunity to the
spread of cancer. Consider the cytotoxic drugs for example. What if we get something that will kill the cell? It
may kill the cancer cell but what else will it kill and
what will be the net effect? Immunosuppressive therapy
of the type that we are using so often in the treatment
of patients with cancer may have an effect exactly opposite from the one we are trying to bring out. Any
immunity that the patient may have to the cancer may
be sharply reduced or completely abrogated by the giving of the cytotoxic agents.’’
—George Crile, Jr. (1966)161
Although the natural history of cancer, especially
that of HNSCC, indicates that withholding therapy of all
kinds would generally result in or expedite the death of
the patient, the concerns expressed above reinforce that
we must consider the effects of current standard treatment on the immune system if we accept that the
immune system plays a role in natural resistance to
cancer.
Surgery. Surgery has been dubbed the ‘‘original
immunotherapy’’ in that surgical extirpation removes
the bulk of disease and allows the immune system to
effectively scavenge and eliminate minimal residual disease.161,162 However, several studies have demonstrated
an immunosuppressive effect following surgery or general anesthesia. Surgical stress induces a broad but
temporary suppression of T-lymphocyte and NK cell activity that is probably mediated by adrenocorticoid
release.163–165 This stress-associated affect is not
specific for surgery but to any major stressor, including
anesthesia and perioperative pain.166 Further immunosuppression in the local resection bed can come from
cytokine release following tissue manipulation. Cytokines such as TGF-b, IL-1, and IL-6 and growth factors
such as EGF and VEGF are not only involved in wound
healing but can promote a malignant phenotype in residual cancer cells and induce local immunosuppression via
generation of a Th2 type cytokine profile.157,167,168 Yet
most of these studies are based on abdominal surgery,
and several studies have demonstrated that minimally
invasive surgery (laparoscopy) induces less local immunosuppression that open surgery (laparotomy).168 A
corollary to these data could be the use of minimally
invasive head and neck cancer resection techniques,
such as transoral laser microsurgery or robotic surgery,
compared to large, open, transcervical tumor resections.
Aside from resecting primary disease burden, head and
neck surgical oncologists commonly perform lymphadenectomy to control regional disease. Although regional
Allen et al.: Immunobiology Head and Neck Cancer
lymph nodes have the capacity to mount antitumor
immune responses against primary tumors,169 whether
lymphadenectomy leads to further depression of such
immune responses is unclear and poorly studied.
Although data specifically evaluating different HNSCC
surgical techniques such as those listed above is lacking,
evidence exists that general surgical stress during and
after primary tumor resection induces a significant but
transient depression in cellular immunity.
Chemotherapy. Chemotherapeutic agents, including platinum-based agents commonly used to treat
HNSCC, are immunosuppressive. Effects on both innate
and adaptive immunity are apparent and commonly
include profound myelosuppression with the risk of sepsis and death during a neutropenic nadir.170 Lymphocyte
suppression has also been demonstrated with cisplatin
therapy,171 and peripheral immune cells from HNSCC
patients secrete less IL-12 and Th1 cytokines including
IFN-c when treated in vitro with cisplatin.172 Yet, the
addition of chemotherapeutic agents has become the
standard in several protocols demonstrating improved
disease control in advanced HNSCC.159 Mechanistically,
this may be explained at least in part by recent work
demonstrating that platinum based chemotherapy
agents have the ability to induce tumor cell surface
expression of antigenic motifs, such as CEA, leading to
enhanced CEA-specific antitumor CTL responses in
vitro.173 Additionally, tumor cell damage secondary to
chemotherapy may induce expression of DAMPs, further
enhancing the immune system’s ability to initiate an
immune response.174 Clearance of HPV-associated SCC
in mice following cisplatin therapy required functional
lymphocytes, further supporting the role of immune recognition of chemotherapy altered tumor cells.175 Clearly
platinum-based chemotherapeutic agents have both
immunosuppressive as well as tumor cell-damaging
effects, and the net pro-tumor or antitumor effect on the
host as a whole as well as the overall utility of these
nonspecific systemic agents must be considered as we
move forward with the development of more targeted
antitumor biological therapies.
Radiotherapy. Although the short- and long-term
adverse effects of radiotherapy are readily identified,176
the systemic effects of localized radiotherapy are often
not considered. Lymphocytes, as well many other cells of
hematopoietic origin, are exquisitely sensitive to ionizing
radiation.177 In mice, total-body irradiation with doses
as low as 2 Gy induced apoptosis in all fractions of
immune cells studied including DCs, NK cells, B-lymphocytes, and CD4þ and CD8þ T-lymphocytes.178
Accordingly, radiation therapy is often used as treatment
for non-Hodgkin’s lymphomas, further illustrating lymphocyte sensitivity to radiotherapy.179 Although
enhanced localization of radiotherapy used to treat
HNSCC is achieved with intensity-modulated radiotherapy (IMRT), systemic immunosuppression, especially of
T-lymphocyte activity and response to antigen, has been
documented in several classic articles.180–183 This systemic effect has been hypothesized to be due to the
irradiation of large volumes of circulating blood passing
through the therapy fields during treatment. Yet, even
Laryngoscope 122: January 2012
more so than chemotherapy, the use of radiotherapy has
long been a critical primary or adjuvant treatment modality for HNSCC. Very similar to chemotherapy,
experimental evidence suggests that radiotherapy
enhances the antigenicity of tumor cells via upregulated
expression of cell surface proteins such as CEA, leading
to enhanced CTL lysis.173,184 A balance exists between
induction of apoptosis in immune cells, subsequent
immune cell recovery, and enhanced tumor cell antigenicity, all induced by radiotherapy. With the widespread
use of IMRT to limit radiation doses to normal tissue adjacent to malignancies, further work is needed to
evaluate if this new modality has less suppressive effects
on circulating immune cells.
As we consider the antitumor and pro-tumor (immunosuppressive) effects of standard therapies to treat
HNSCC, we realize a potential explanation for why current therapeutics for carcinogen-associated HNSCC
appear to have reached a plateau. A patient’s response to
standard anticancer therapy will be determined by the
balance between antitumor effects of the natural immune
response, surgical extirpation of malignant disease, and
antitumor effects of chemotherapy and radiotherapy versus pro-tumor immunosuppression mediated by surgery,
chemotherapy, and radiation, as well as tumor cell-mediated immunosuppression and intrinsic resistance to
chemical or radiotherapy (Fig. 2). New therapies aimed at
modulating pro-tumor effects or enhancing antitumor
effects may durably alter the balance in favor of the host
and result in improved patient outcomes.
Immunotherapy for HNSCC
The development of immunotherapeutic strategies
for HNSCC has developed based upon our understanding of TAA expression and their ability to generate a
specific antitumor response. Below, we discuss the rationale for the use of individual and grouped cytokine
therapy, monoclonal antibody therapy, and viral oncolytic therapy, as well as the development of tumor
vaccines designed to treat patients with HNSCC.
Enhancing natural antitumor immune
responses through cytokine delivery.
Locally or systemically administered cytokines
rationally selected to enhance cytotoxic antitumor immunity have been investigated. In a murine oral cancer
model, administration of plasmid-encoded IL-2 in a cationic lipid carrier resulted in increased intratumoral
expression of antitumor Th1 cytokines.185 Used in the
perioperative period, peritumoral lymph node injection
of IL-2 resulted in improved disease free survival in
multivariate analysis.186 Systemic injection of IFN-c,
along with the related IFN-a, as adjuvant therapies
have resulted in variable clinical efficacies.187–189 Intratumoral injection of IL-12 resulted in increased IFN-c,
NK cell recruitment, and a Th2 to Th1 cytokine profile
switch in tumor draining lymph nodes.190
Combination immunotherapy combining a panel of
selected cytokines and immunomodulators has been
Allen et al.: Immunobiology Head and Neck Cancer
151
Fig. 2. Diagram illustrating factors involved in controlling the balance between tumor elimination and progression in patients with
head and neck cancer. [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
hypothesized to compound and amplify clinical responses.
IRX-2 is a cell-free mixture of cytokines designed to
enhance natural immune responses.191 IRX-2 has been
reported to expand intratumoral and draining lymph
node lymphocyte populations in HNSCC patients,192,193
induce DC maturation,194 inhibit FasL-mediated T-lymphocyte apoptosis in vitro,195 and enhance T-lymphocyte
recognition of TAA and subsequent antitumor response to
tumor challenge in mice.196 Patients with mixed-stage
HNSCC given preoperative IRX-2 demonstrated modest
improvements in recurrence and survival rates.197 Given
the preclinical and clinical results detailed above, phase
II and III clinical trials are investigating the clinical efficacy of several individual cytokines as well as IRX-2 in
patients with advanced HNSCC.191
Monoclonal antibody therapy. The recognition
that EGFR was overexpressed on the majority of
HNSCC cells provided a rationale for the use of antiEGFR therapies.198,199 Cetuximab, a chimeric monoclonal antibody (mAb) targeting the extracellular portion of
EGFR, was found to enhance survival when combined
with radiotherapy in patients with advanced HNSCC.200
However, subsequent analysis has revealed that only
30% of patients respond to cetuximab and that this
response does not correlate with level of EGFR expression or inhibition of pro-growth and pro-survival
signaling pathways downstream of EGFR.198,201 Further,
tumors shown to have no dependence on EGFR for
growth or survival respond to cetuximab.202 Interestingly, clinical response to cetuximab has been closely
correlated with the development of a skin rash, suggesting a systemic effect in only a subset of patients.203 As
first shown for rituximab, subsequent studies revealed
that HNSCC tumor cell killing in response to cetuximab
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152
occurs at least in part through NK cell-mediated antibody-dependent cellular cytotoxicity,199,204,205 and that
the presence of a specific Fc receptor polymorphism can
further predict cetuximab cytotoxicity.206 This understanding provides a framework for understanding, at
least in part, the mechanism of action of other antibodybased therapies such as the anti-EGFR humanized mAb
panitumumab and the anti-VEGF mAb bevacizumab.
Bevacizumab has shown significant antitumor activity
when combined with paclitaxel in a mouse xenograft
model.207 Several clinical trial investigating the role of
bevacizumab are underway including a phase III multiinstitutional, randomized, controlled trial comparing
chemotherapy plus bevacizumab to chemotherapy alone
in patients with recurrent or metastatic HNSCC.191
Viral oncolytic therapy. The herpes simplex virus
(HSV) has been studied as an anticancer therapeutic
extensively due to its ability to undergo lytic viral replication, resulting in destruction of the infected cell.
OncoVEXGM-CSF is such a virus constructed to also
express GM-CSF as an adjuvant, chosen for its myeloid
cell recruiting and DC maturation properties. An OncoVEXGM-CSF phase I proof-of-concept and feasibility
study,208 as well as a phase II study demonstrating a
high locoregional control rate in patients with advanced
HNSCC209 have been performed. Future large-scale
studies may reveal the potential role of this viral immunotherapy designed to alter the antigenicity of tumor
cells in patients with advanced HNSCC.
Tumor vaccines. Vaccination can be categorized as
preventative or therapeutic. Preventative vaccines have
been demonstrated to be highly efficacious against
pathogens, and the role of viral-like particle (VLP) based
vaccines in the prevention of viral-associated HNSCC,
such as HPV-associated oropharyngeal SCC, will be
revealed with time.210 Much work has focused on the
treatment of HNSCC with therapeutic vaccines, which
can be functionally divided into autologous immune cell
transfer and peptide/protein-based vaccines.211
The term adoptive autologous cell transfer refers to
the process of removing a host’s immune cells, modifying
them in some manner to induce antigen specific immune
responses, and reinjecting them into the same host’s
circulation. Recent FDA approval of Sipuleucel-T (Provenge) for advanced prostate cancer, a therapeutic
cancer vaccine where autologous DCs are incubated with
a prostate cancer TAA (prostatic acid phosphatase)
linked with GM-CSF and reinjected, has demonstrated
the clinical safety and feasibility of such methods in a
clinical setting.212 In two similar proof-of-concept studies, patients with advanced or recurrent HNSCC were
injected with irradiated autologous tumor cells plus adjuvant, lymphocytes from draining lymph nodes were
harvested and expanded and reinjected with subsequent
immunologic responses, demonstrating the feasibility of
adoptive T-cell transfer.213,214 Based upon these results,
several clinical trials utilizing adoptive cell transfer
techniques to load DCs with TAAs such as p53 and
EGFR and tumor-associated proteins such as CEA in the
treatment of advanced HNSCC are currently
underway.191,215
Allen et al.: Immunobiology Head and Neck Cancer
Criticisms of adoptive cell transfer-based therapeutics include technical feasibility of implementing such
laborious methods in large-scale studies and eventual
clinical practice.211 Peptide-based vaccines, which can be
standardized and easily administered, overcome some of
these practical issues. These vaccines consist of individual TAAs or tumor-associated proteins linked with
various adjuvants to stimulate or facilitate APC uptake,
antigen processing, and presentation and development of
antigen-specific immune responses. TAAs such as p53,
MAGE proteins, and HPV-associated proteins have all
been linked with a host of adjuvants to generate vaccine
constructs designed to treat HNSCC.4,191,211,216 The majority of trials investigating the tolerability and clinical
efficacy of these peptide-based vaccines are in early
phases and address the effects of these vaccines as
monotherapy or in combination with existing anticancer
therapies.211 Future design and development of modifiable tumor therapeutic vaccines based upon the
presence or absence of specific TAAs and the corresponding MHC restrictions for antigen presentation may allow
for highly individualized anticancer vaccines. The modest clinical response to tumor vaccines demonstrated in
HNSCC patients thus far has been attributed to the robust immunosuppression observed within the HNSCC
patients,4,217 and successful future application of such
therapeutics will likely involve combination therapy
designed to both target the tumor cells as well as modulate the tumor-permissive microenvironment.
FUTURE DIRECTIONS
Critical to the progression of our understanding of
the interaction between immune and cancer cells in the
tumor microenvironment is the development of appropriate mouse models. Many xenograft models exist that
allow for the molecular dissection of human HNSCC tumor cell growth and metastasis in vivo.218 Although
xenograft models allow for the study of human tumor
cell lines, the immunodeficient host mouse is unable to
mount an anti-tumor response. Syngeneic models of carcinogen-induced HNSCC in fully immunocompetent mice
are needed to characterize and investigate methods of
modifying immune cell infiltrate and function.
As preclinical experiments and clinical trials move
forward evaluating the ability to induce antitumor immunity in patients, several interesting and related areas
of HNSCC research exist. Over the last 10 years, clinicians have recognized a distinct subset of oropharyngeal
SCC (OPSCC) associated not with carcinogen use but
with biologically active HPV. These HPV-associated
OPSCCs appear to be a molecularly distinct subset of
cancers, and patients with HPV-associated OPSCC have
dramatically improved survival and locoregional tumor
control compared to carcinogen-associated OPSCC.158
Although carcinogen-associated OPSCC may express
TAAs capable of eliciting a specific antitumor immune
response, HPV-associated OPSCC contain within their
proteome highly antigenic HPV-associated oncoproteins
such as E6 and E7 that serve as potent TAAs.80,81,219
Evidence in the cervical cancer and HNSCC literature
Laryngoscope 122: January 2012
suggests that a robust in vitro and in vivo immune
response
to
HPV-associated
antigenic
material
exists.80,81,158,219,220 HPV-associated OPSCC therefore
represents a natural model of enhanced antitumor
immune responses against highly antigenic tumor cells.
Current and future studies detailing this robust immune
response, and which immune cells are critical for its
antitumor effects, may provide powerful information
that could be utilized to enhance antitumor immune
responses against the more prevalent carcinogen-associated HNSCC.
Another compelling topic of research in HNSCC is
the theory of cancer stem cells (CSCs). Evidence is
mounting that these progenitor cells are the targets of
genetic aberrations that lead to squamous cell transformation and are the minor population of cells within a
heterogeneous HNSCC tumor that are tumor initiating.221 Further, these cells are hypothesized to be highly
resistant to therapy and may mediate tumor persistence
or recurrence after anticancer therapy.222,223 Experimental evidence demonstrates that NK cells, cdT cells and
CTLs have the ability to recognize cancer stems cells in
vitro,224 yet to date, few studies have examined the inherent antigenicity of these highly tumorigenic
progenitor cells in the face of an in vivo anticancer
immune response. Interestingly, high tumor cell aldehyde dehydrogenase expression has been shown to be a
characteristic of HNSCC CSCs,222 and aldehyde dehydrogenase 1-A1 has been shown to be capable of
inducing specific CTL immune responses, acting as a
TAA.72 If future anticancer therapies, including immunomodulatory treatments, cannot be shown to provide a
response against progenitor cells responsible for populating a heterogeneous tumor mass, then these therapies
may have no advantage over current therapeutic strategies in terms of eradication of minimal residual
disease.
CONCLUSIONS
Although the dysregulated pro-growth and pro-survival signaling pathways that promote a malignant
phenotype in HNSCC have been studied extensively
over the last 20 years, detailed analysis of the mechanisms of immune response to HNSCC tumorigenesis is
in its early stages. Further understanding of the mechanisms that lead to immune escape of and tolerance to
HNSCC tumor cells, including the link between these
mechanisms and known dysregulated signaling within
the tumor cells, will likely provide further opportunity
for therapeutic intervention. Multiple mechanisms of tumor cell-induced local and systemic immune suppression
pose a formidable barrier to the success of current and
investigational immune-based therapeutics. Enhanced
understanding of the fundamental concepts that contribute to the tumor-induced immunosuppressive
microenvironment, such as antigenic tolerance and tissue-specific mechanisms of TAA presentation to immune
effector cells, may allow for the rational design of immunomodulatory agents to treat both locoregional and
metastatic disease. Conceptually, future treatment
Allen et al.: Immunobiology Head and Neck Cancer
153
regimens may need to incorporate combination therapy
aimed at both enhancing antitumor immunity while
abrogating both tumor cell and standard antitumor therapy-induced immunosuppression in the setting of
minimal residual disease.
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