Cancer is a major health problem worldwide and one of the most important causes of morbidity and mortality in children and adults. The lethality of malignant tumors is due to their uncontrolled growth within normal tissues, causing damage and functional impairment. The malignant phenotype of cancers reflects defects in regulation of cell proliferation, resistance of the tumor cells to apoptotic death, ability of the tumor cells to invade host tissues and metastasize to distant sites, and tumor evasion of host immune defense mechanisms. The existence of immune surveillance has been demonstrated by the increased incidence of some types of tumors in immunocompromised experimental animals and humans. It is now clear that the innate and adaptive immune systems do react against many tumors, and exploiting these reactions to specifically destroy tumors remains an important goal of tumor immunologists. Several characteristics of tumor antigens and immune responses to tumors are fundamental to an understanding of tumor immunity and for the development of strategies for cancer immunotherapy.
The existence of specific anti-tumor immunity implies that tumors must express antigens that are recognized as foreign by the host. The earliest classification of tumor antigens was based on their patterns of expression. Antigens that are expressed on tumor cells but not on normal cells are called tumor-specific antigens; some of these antigens are unique to individual tumors, whereas others are shared among tumors of the same type. Tumor antigens that are also expressed on normal cells are called tumor-associated antigens; in most cases, these antigens are normal cellular constituents whose expression is aberrant or dys-regulated in tumors. The modern classification of tumor antigens is based on the molecular structure and source of antigens expressed by tumor cells that stimulate T cell or antibody responses in their hosts (Table 1).
1. Products of Mutated Genes
Oncogenes and mutated tumor suppressor genes produce proteins that differ from normal cellular proteins and, therefore, can induce immune responses. Many tumors express genes are produced by point mutations, deletions, chromosomal translocations, or viral gene insertions affecting cellular proto-oncogenes or tumor suppressor genes. The products of many of these mutant oncogenes and tumor suppressor genes are cytosolic or nuclear proteins that are degraded in proteasomes and can be presented on class I MHC molecules in tumor cells. These proteins may enter the MHC class I and class II antigen presentation pathways in dendritic cells that have phagocytosed dead tumor cells or apoptotic bodies derived from tumor cells.
Tumor antigens may be produced by randomly mutated genes whose products are not related to the malignant phenotype. Tumor antigens that were defined by the transplantation of carcinogen-induced tumors in animals, called tumor-specific transplantation antigens, are mutants of various host cellular proteins. These antigens are extremely diverse because the carcinogens that induce the tumors may randomly mutagenize any host gene, and the class I MHC antigen-presenting pathway can display peptides from any mutated cytosolic protein in each tumor.
2. Abnormally Expressed but Unmutated Cellular Proteins
Tumor antigens that elicit immune responses may be normal cellular proteins that are abnormally expressed in tumor cells. Many such antigens have been identified in human tumors, such as melanomas, by the molecular cloning of antigens that are recognized by T cells and antibodies from tumor-bearing patients. One of the surprises that emerged from these studies was that some tumor antigens are unmutated proteins that are produced at low levels in normal cells and overexpressed in tumor cells.
Cancer/testis antigens are proteins expressed in gametes and trophoblasts and in many types of cancers but not in normal somatic tissues. The first cancer/testis antigens were identified by cloning genes from human melanomas that encoded cellular protein antigens recognized by melanoma-specific CTL clones derived from the melanoma-bearing patients. These were called MAGE proteins, and they were subsequently found to be expressed in other tumors in addition to melanomas, including carcinomas of the bladder, breast, skin, lung, and prostate and some sarcomas, as well as in normal testes. In general, they are not required for the malignant phenotype of the cells, and their sequences are identical to the corresponding genes in normal cells; that is, they are not mutated. Several X-linked cancer/testis antigens are currently being used in tumor vaccine trials.
3. Antigens of Oncogenic Viruses
The products of oncogenic viruses function as tumor antigens and elicit specific T cell responses that may serve to eradicate the tumors. DNA viruses are implicated in the development of a variety of tumors in humans and experimental animals. Examples in humans include the Epstein-Barr virus (EBV), which is associated with B cell lymphomas and nasopharyngeal carcinoma; human papillomavirus (HPV), which is associated with carcinomas of the uterine cervix, oropharynx, and other sites; and Kaposi sarcoma–associated herpesvirus (KSHV/ HHV-8), which is associated with vascular tumors. Papovaviruses, including polyomavirus and simian virus 40 (SV40), and adenoviruses induce malignant tumors in neonatal or immunodeficient adult rodents. In most of these DNA virus–induced tumors, virus-encoded protein antigens are found in the nucleus, cytoplasm, or plasma membrane of the tumor cells. These endogenously synthesized viral proteins can be processed and presented by MHC molecules on the tumor cell surface. Because the viral peptides are foreign antigens, DNA virus–induced tumors are among the most immunogenic tumors known.
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. It is believed that the genes encoding these proteins are silenced during development and are derepressed with malignant transformation. Oncofetal antigens are identified with antibodies raised in other species, and their main importance is that they provide markers that aid in tumor diagnosis. However, their expression in adults is not limited to tumors, but is increased in tissues and in the circulation in various inflammatory conditions, and the antigens are found in small quantities even in normal tissues. There is no evidence that oncofetal antigens are important inducers or targets of antitumor immunity. The two most thoroughly characterized oncofetal antigens are carcinoembryonic antigen (CEA) and α-fetoprotein (AFP).
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. Some aspects of the malignant phenotype of tumors, including tissue invasion and metastatic behavior, may reflect altered cell surface properties that result from abnormal glycolipid and glycoprotein synthesis. Many antibodies have been raised in animals that recognize the carbohydrate groups or peptide cores of these molecules. Although most of the epitopes recognized by these antibodies are not specifically expressed on tumors, they are present at higher levels on cancer cells than on normal cells. This class of tumor-associated antigen is a target for cancer therapy with specific antibodies.
6. Tissue-Specific Differentiation Antigens
Tumors may express molecules that are normally expressed only on the cells of origin of the tumors and not on cells from other tissues. These antigens are called differentiation antigens because they are specific for particular lineages or differentiation stages of various cell types. Their importance is as potential targets for immunotherapy and for identification of the tissue of origin of tumors.
Table 1. Tumor Antigens
|Type of Antigen||Examples of Human Tumor Antigens|
|Products of mutated oncogenes, tumor suppressor genes||Oncogene products: Ras mutations (∼10% of human carcinomas), p210 product of Bcr/Abl rearrangements; (CML) Tumor suppressor gene products: mutated p53 (present in ∼50% of human tumors)|
|Unmutated but overexpressed products of oncogenes||HER2/Neu (breast and other carcinomas)|
|Mutated forms of cellular genes not involved in tumorigenesis||Various mutated proteins in melanomas recognized by CTLs|
|Products of genes that are silent in most normal tissues||Cancer/testis antigens expressed in melanomas and many carcinomas; normally expressed mainly in the testis and placenta|
|Normal no oncogenic proteins overexpressed in tumor cells||Tyrosinase, gp100, MART in melanomas (normally expressed in melanocytes)|
|Products of oncogenic viruses||Papillomavirus E6 and E7 proteins (cervical carcinomas) EBNA-1 protein of EBV (EBV-associated lymphomas, nasopharyngeal carcinoma)|
|Oncofetal antigens||Carcinoembryonic antigen on many tumors, also expressed in liver and other tissues during inflammation α-Fetoprotein|
|Glycolipids and glycoproteins||GM2, GD2 on melanomas|
|Differentiation antigens normally present in tissue of origin||Prostate-specific antigen in prostate carcinomas CD20 on B cell lymphomas|
Immune Responses to Tumors
Adaptive immune responses, mainly mediated by T cells, have been shown to control the development and progression of malignant tumors. Both innate and adaptive immune responses can be detected in patients and experimental animals, and various immune mechanisms can kill tumor cells in vitro. The challenge for tumor immunologists is to determine which of these mechanisms may contribute significantly to protection against tumors and to enhance these effector mechanisms in ways that are tumor specific. (Figure 1)
1. T Lymphocytes
The principal mechanism of adaptive immune protection against tumors is killing of tumor cells by CD8+ CTLs. CTLs may perform a surveillance function by recognizing and killing potentially malignant cells that express peptides that are derived from tumor antigens and are presented in association with class I MHC molecules. CD8+ T cell responses specific for tumor antigens may require cross-presentation of the tumor antigens by dendritic cells. Most tumor cells are not derived from APCs and therefore do not express the costimulators needed to initiate T cell responses or the class II MHC molecules needed to stimulate helper T cells that promote the differentiation of CD8+ T cells. A likely explanation of how T cell responses to tumors are initiated is that tumor cells or their antigens are ingested by host APCs, particularly dendritic cells, and tumor antigens are processed inside the APCs. Peptides derived from these antigens are then displayed bound to class I MHC molecules for recognition by CD8+ T cells. The APCs express costimulators that provide the signals needed for differentiation of CD8+ T cells into anti-tumor CTLs.
The importance of CD4+ helper T cells in tumor immunity is less clear. CD4+ cells may play a role in anti-tumor immune responses by providing cytokines for differentiation of naive CD8+ T cells into effector and memory CTLs. In addition, 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.
Tumor-bearing hosts may produce antibodies against various tumor antigens. For example, patients with EBV associated lymphomas have serum antibodies against EBV-encoded antigens expressed on the surface of the lymphoma cells. Antibodies may kill tumor cells by activating complement or by antibody-dependent cell-mediated cytotoxicity, in which Fc receptor–bearing macrophages or NK cells mediate the killing. However, the ability of antibodies to eliminate tumor cells has been demonstrated largely in vitro, and there is little evidence for effective humoral immune responses against tumors.
3. Natural Killer Cell
NK cells kill many types of tumor cells, especially cells that have reduced class I MHC expression and express ligands for NK cell–activating receptors. The importance of NK cells in tumor immunity in vivo is unclear. In some studies, T cell–deficient mice do not have a high incidence of spontaneous tumors, and this is attributed to the presence of normal numbers of NK cells that serve an immune surveillance function.
Macrophages are capable of both inhibiting and promoting the growth and spread of cancers, depending on their activation state. Classically activated M1 macrophages, discussed in Chapter 10, can kill many tumor cells. How macrophages are activated by tumors is not known. Possible mechanisms include recognition of damage-associated molecular patterns from dying tumor cells by macrophage TLRs and other innate immune receptors, and activation of macrophages by IFN-γ produced by tumor-specific T cells. M1 macrophages can kill tumor cells by mechanisms that they also use to kill infectious organisms.
There is evidence that some macrophages in tumors contribute to tumor progression and have an M2 phenotype. These cells secrete vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and other soluble factors that promote tumor angiogenesis.
Figure 1. Immune response to tumor.
Evasion of Immune Responses by Tumors
Many cancers develop mechanisms that allow them to evade anti-tumor immune responses. These mechanisms can broadly be divided into those that are intrinsic to the tumor cells and those that are mediated by other cells (Fig. 2). A major focus of tumor immunology is to understand the immune evasion mechanisms of tumors, with the hope that interventions to prevent immune evasion will increase the immunogenicity of tumors and maximize the responses of the host.
1. Escaping Immune Recognition by Loss of Antigen Expression
Immune responses to tumor cells impart selective pressures that result in the survival and outgrowth of variant tumor cells with reduced immunogenicity, a process that has been called tumor immunoediting. Tumors developing in the setting of a normal immune system become less immunogenic over time, which is consistent with the selection of less immunogenic variant cells. Given the high mitotic rate of tumor cells and their genetic instability, mutations or deletions in genes encoding tumor antigens are common. If these antigens are not required for growth of the tumors or maintenance of the transformed phenotype, the antigen-negative tumor cells will have a growth advantage in the face of the host immune system. Thus, tumor immunoediting is thought to underlie the emergence of tumors that escape immune surveillance.
In addition to loss of tumor-specific antigens, class I MHC expression may be down-regulated on tumor cells so that they cannot be recognized by CTLs. Various tumors show decreased synthesis of class I MHC molecules, β2-microglobulin, or components of the antigen processing machinery, including the transporter associated with antigen processing and some subunits of the proteasome. These mechanisms are presumably adaptations of the tumors that arise in response to the selection pressures of host immunity, and they may allow tumor cells to evade T cell–mediated immune responses.
2. Active Inhibition of Immune Responses
Tumors may engage inhibitory mechanisms that suppress immune responses. There is strong experimental and clinical evidence that T cell responses to some tumors are inhibited by the involvement of CTLA-4 or PD-1, two of the best-defined inhibitory pathways in T cells. Secreted products of tumor cells may suppress antitumor immune responses. Regulatory T cells may suppress T cell responses to tumors. Tumor-associated macrophages may promote tumor growth and invasiveness by altering the tissue microenvironment and by suppressing T cell responses. 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 anti-tumor innate and T cell responses.
Figure 2. Evasion mechanisms of immune responses by tumors.
Immunotherapy for Tumors
The potential for treatment of cancer patients by immunologic approaches has held great promise for oncologists and immunologists for many years. The main reason for interest in an immunologic approach is that most current therapies for cancer rely on drugs that kill dividing cells or block cell division, and these treatments have harmful effects on normal proliferating cells. As a result, the treatment of cancers causes significant morbidity and mortality. Immune responses to tumors may be specific for tumor antigens and will not injure most of the normal cells. Therefore, immunotherapy has the potential of being the most tumor-specific treatment that can be devised. Advances in our understanding of the immune system and in defining antigens on tumor cells have encouraged many new strategies. Immunotherapy for tumors aims to augment the weak host immune response to the tumors (active immunity) or to administer tumor-specific antibodies or T cells, a form of passive immunity.
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