Download immune responses to tumors

Chapter 18
Immunity to Tumors
•
Cancer is a major health problem worldwide and one of the most important
causes of morbidity and mortality in children and adults
•
Cancers arise from the uncontrolled proliferation and spread of clones of
transformed cells
•
Benign and Malignant tumors, Metastases
•
Immune surveillance (physiologic function of the immune System),
Macfarlane Burnet 1950s
General Features of Tumor Immunity
• Tumors stimulate specific, adaptive immune responses
 many tumors are surrounded by mononuclear cell infiltrates composed
of T lymphocytes, natural killer (NK) cells, and macrophages, and that
activated lymphocytes and macrophages are present in lymph nodes
draining the sites of tumor growth
• The first experimental demonstration that tumors can induce protective
immune responses came from studies of transplanted tumors performed
in the 1950s (Methylcholanthrene, MCA)
•
Immune responses frequently fail to prevent the growth of tumors:
– First, tumor cells are derived from host cells (weakly immunogenic)
– Second, the rapid growth and spread of tumors
– Third, many tumors have specialized mechanisms for evading host
•
The immune system can be activated by external stimuli to effectively kill
tumor cells and eradicate tumors (immunotherapy)
Tumor antigens
•
The earliest classification of tumor antigens was based on their patterns of
expression
– tumor-specific antigens: Antigens that are expressed on tumor cells but not on normal
cells
– tumor-associated antigens: Tumor antigens that are also expressed on normal cells
•
The modern classification of tumor antigens relies on the molecular structure and
source of the antigens
•
To purify and characterize these antigens were based on producing monoclonal
antibodies specific for tumor antigens
•
A more recently developed approach for identification of tumor antigens
specifically is called serologic analysis of recombinant cDNA expression (SEREX)
•
Tumor antigens (peptides) that are recognized by T cells are likely to be the major
inducers of tumor immunity and the most promising candidates for tumor
vaccines
1) Products of Mutated Genes
•
Tumor antigens are produced by oncogenic mutants of normal cellular
genes
•
Often, these genes are produced by point mutations, deletions,
chromosomal translocations, or viral gene insertions affecting cellular protooncogenes or tumor suppressor genes
•
Peptides derived from them do not induce self-tolerance (circulating
CD4+and CD8+T cells that can respond to them)
•
Mutated oncogenes such as Ras and Bcr-Abl proteins and mutated tumor
supressor genes such as p53
P53 gene
2) Abnormally Expressed Cellular Proteins
•
Normal cellular proteins that are abnormally expressed in tumor cells and
elicit immune responses
•
One such antigen is tyrosinase, an enzyme involved in melanin biosynthesis
that is expressed only in normal melanocytes and melanomas
•
Tyrosinase-specific T or tyrosinase vaccines
•
Cancer/testis antigens are proteins expressed in gametes and trophoblasts,
and in many types of cancers, but not in normal somatic tissues (MAGE
proteins expressed in other tumors in addition to melanomas, including
carcinomas of the bladder, breast, skin, lung, and prostate, and some
sarcomas)
3) Antigens of Oncogenic Viruses
•
The products of oncogenic viruses (DNA viruses) function as tumor antigens
and elicit specific T cell responses that may serve to eradicate the tumors
•
Epstein-Barr
carcinoma,
•
Human papillomavirus (HPV), cervical carcinoma
•
Papovaviruses, including polyomavirus and simian virus 40 (SV40), and
adenoviruses induce malignant tumors
•
Because the viral peptides are foreign antigens, DNA virus-induced tumors
are among the most immunogenic tumors known
virus
(EBV),
B
cell
lymphomas
and
nasopharyngeal
•
RNA tumor viruses (retroviruses) are important causes of tumors in animals
•
Human retrovirus that is known to cause tumors is human T cell
lymphotropic virus 1 (HTLV-1), adult T cell leukemia/lymphoma (ATL), a
malignant tumor of CD4+ T cells
•
Patients with ATL are often profoundly immunosuppressed, probably
because the virus infects CD4+ T cells
4) Oncofetal Antigens
•
Oncofetal antigens are proteins that are expressed at high levels in cancer
cells and in normal developing fetal but not adult tissues
•
These antigens are increased in tissues and in the circulation in various
inflammatory conditions and are found in small quantities even in normal
tissues
•
Carcinoembryonic antigen (CEA) and α-fetoprotein (AFP)
 Carcinoembryonic antigen (CEA):
• CEA (CD66) is a highly glycosylated integral membrane protein, of the
immunoglobulin (lg) superfamily, an intercellular adhesion molecule that
functions to promote the binding of tumor cells
•
High CEA expression is normally restricted to cells in the gut, pancreas, and
liver during the first two trimesters of gestation, and low expression is seen
in normal adult colonic mucosa and the lactating breast
•
CEA expression is increased in many carcinomas of the colon, pancreas,
stomach, and breast
•
The level of serum CEA is used to monitor the persistence or recurrence of
the tumors after treatment
 AFP is a circulating glycoprotein normally synthesized and secreted in fetal
life by the yolk sac and liver
•
Elevated in patients with hepatocellular carcinoma, germ cell tumors, and,
occasionally, gastric and pancreatic cancers
•
useful indicator of advanced liver or germ cell tumors or of recurrence
5) Altered Glycolipid and Glycoprotein Antigens
•
Most human and experimental tumors express higher than normal levels or
abnormal forms of surface glycoproteins and glycolipids, which may be
diagnostic markers and targets for therapy
•
These altered molecules include gangliosides, blood group antigens, and
mucins
•
Melanomas are the gangliosides GM2, GD2, and GD3
•
Clinical trials immunotherapy of anti-GM2, anti-GD3 and anti-GM2
antibodies in melanoma
•
Mucins including CA-125 and CA-19-9, expressed on ovarian carcinomas,
and MUC-1, expressed on breast carcinomas
Ovarian ca
6) Tissue-Specific Differentiation Antigens
•
Tumors express molecules that are normally present on the cells of origin
called differentiation antigens
•
Several melanoma antigens that are targets of CTLs in patients are
melanocyte differentiation antigens, such as tyrosinase
•
Lymphomas may be diagnosed as B cell-derived tumors as CD10
(previously called common acute lymphoblastic leukemia antigen, or
CALLA) and CD20
•
Ig idiotype is a highly specific tumor antigen for B cell lymphomas and
leukemias
IMMUNE RESPONSES TO TUMORS
Innate immune response to tumors
1. NK Cells
•
NK cells kill many types of tumor cells, especially cells that reduced class I
MHC expression
•
ADCC with FCγRIII
•
The tumoricidal capacity of NKC is increased by cytokines, including
interferons and interleukins (lL-2 and IL-12)
•
lymphokine- activated killer (LAK) cells as adoptive immunotherapy, IL-2
•
2. Macrophages
In vitro, activated macrophages can kill many tumor cells more efficiently
than they can kill normal cells
•
Possible mechanisms include direct recognition of some surface antigens of
tumor cells and activation of macrophages by lFN-γ produced by tumorspecific T cells
•
Activated macrophages also produce the cytokine tumor necrosis factor
(TNF)
Adaptive Immune Responses to Tumors
•
•
Both T cell-mediated and humoral immune responses
1. T Lymphocytes
The principal mechanism of tumor immunity is killing of tumor cells by CD8+
CTLs that associate with class I MHC molecules
•
CD8+T cell responses specific for tumor antigens may require cross
presentation of the tumor antigens by professional APCs, such as dendritic
cells in class II MHC
•
APCs express class II MHC molecules that may present internalized tumor
antigens and activate CD4+ helper T cells
•
Helper T cells specific for tumor antigens may secrete cytokines, such as
TNF and IFN-γ, that can increase tumor cell class I MHC expression and
sensitivity to lysis by CTLs
2. Antibodies
•
Against various tumor antigens, as EBV-encoded antigens expressed on
the surface of the lymphoma cells
•
Antibodies may kill tumor cells by activating complement or ADCC
Evasion of Immune Responses by Tumors
•
Reduced immunogenicity, a process that has been called "tumor editing“
•
Tumor antigens may induce specific immunological tolerance
•
Regulatory T cells may suppress T cell responses to tumors
•
Tumors lose expression of antigens that elicit immune responses
•
Tumors may fail to induce CTLs because most tumor cells do not express
costimulators or class II MHC molecules
•
The products of tumor cells may suppress anti-tumor immune responses, as
TGF-β or Some tumors express Fas ligand (FasL), glycocalyx molecules
Tumors escape immune defenses
Extrinsic Cellular Suppression of
Anti-Tumor Immunity
• Tumor-associated macrophages (M2 phenotype) may
promote tumor growth and invasiveness by altering the tissue
microenvironment and by suppressing T cell responses
• Regulatory T cells may suppress T cell responses to tumors
• Myeloid-derived suppressor cells (MDSCs) are immature
myeloid precursors that are recruited from the bone marrow
and accumulate in lymphoid tissues, blood, or tumors of
tumor-bearing animals and cancer patients and suppress antitumor innate and T cell responses
Immunotherapy for Tumors
•
Treating cancer has held great promise for oncologists and immunologists
specific for tumor antigens and will not injure most normal cells
•
Immunotherapy for tumors aims active immunity or to administer tumorspecific antibodies or T cells (passive immunity)
Stimulation of Active Host Immune Responses
to Tumors
1. Vaccination with Tumor Cells and Tumor Antigens
•
Immunization with killed tumor cells or tumor antigens
•
Identification of peptides recognized by tumor-specific CTLs
•
And the cloning of genes with injection of plasmids containing cDNAs
encoding tumor antigens (DNA vaccines)
•
Tumor antigens, such as the MAGE, tyrosinase, and gp100 antigens on
melanomas and mutated Ras and p53 proteins are potentially useful
immunogens
•
Virally induced tumors can be blocked by preventive vaccination with viral
antigens or attenuated live viruses
2. Augmentation of Host Immunity with Costimulators and Cytokines
3. Blocking Inhibitory Pathways to Promote Tumor Immunity
•
Inhibitory receptor for B7, called CTLA-4
4. Nonspecific Stimulation of the Immune System
•
local administration of inflammatory substances (BCG) or,
•
Systemic treatment with agents that function as polyclonal activators of
lymphocytes (anti-CD3 antibodies)
Passive Immunotherapy for Tumors with T Cells and
Antibodies
1. Adoptive Cellular Therapy
•
2. Graft-versus-Leukemia Effect
In leukemia patients, administration of alloreactive T cells together with
hematopoietic stem cell transplantscan contribute to eradication of the
tumor
3. Therapy with Anti-tumor Antibodies
•
Tumor-specific monoclonal antibodies (magic bullets) may be useful for
specific immunotherapy for tumors
•
Effector mechanisms including opsonization and phagocytosis and
activation of the complement system
•
Humanized mAB and immunotoxins
Role of immune system in promoting of tumors
•
Chronic inflammation (H. Pylori in gasteric ca. and chronic hepatitis B and C
virus in hepatocellular ca.)
•
Chronic activation of innate immune cells, notably macrophages, is
characterized by angiogenesis and tissue remodeling, both of which favor
tumor formation
•
Innate immune cells can also contribute by generating free radicals that
cause DNA damage and lead to mutations in tumor suppressor genes and
oncogenes
•
Mast cells, neutrophils, and macrophages, secrete soluble factors that
promote celI-cycle progression and survival of tumor cells