Immunity to Tumors for medical and health

best slide to understand role of immune response to fight tumor/cancer cell

1. Immunity to Tumors

2. 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 malignantly transformed cells. The lethality of malignant tumors is determined in large part by their unregulated proliferative activity, the resistance of tumor cells to apoptotic death, and the ability of tumor cells to invade host tissues and metastasize to distant sites. The possibility that cancers can be eradicated by specific immune responses has been the impetus for a large body of work in the field of tumor immunology

3. The concept of immune surveillance, which was proposed by Macfarlane Burnet in the 1950s, states that a physiologic function of the immune system is to recognize and destroy clones of transformed cells before they grow into tumors and to kill tumors after they are formed. The existence of immune surveillance has been demonstrated by the increased incidence of some types of tumors in immunocompromised experimental animals and humans. Although the overall importance of immune surveillance has been controversial, 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.

4. GENERAL FEATURES OF TUMOR IMMUNITY 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.

5. Tumors stimulate specific, adaptive immune responses. Clinical observations and animal experiments have established that although tumor cells are derived from host cells, the tumors elicit immune responses. Histopathologic studies show that 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

6. The first experimental demonstration that tumors can induce protective immune responses came from studies of transplanted tumors performed in the 1950s. A sarcoma may be induced in an inbred mouse by painting its skin with the chemical carcinogen methylcholanthrene (MCA). If the MCA-induced tumor is excised and transplanted into other syngeneic mice, the tumor grows. In contrast, if the tumor is transplanted back into the original host, the mouse rejects the tumor. The same mouse that had become immune to its tumor is incapable of rejecting MCA-induced tumors produced in other mice.

7. Furthermore, T cells from the tumor-bearing animal can transfer protective immunity to the tumor to another tumor-free animal. Thus, immune responses to tumors exhibit the defining characteristics of adaptive immunity , namely, specificity, memory, and the key role of lymphocytes. As predicted from these transplantation experiments, the most effective response against naturally arising tumors appears to be mediated mainly by T lymphocytes.

8. Immune responses frequently fail to prevent the growth of tumors There may be several reasons that antitumor immunity is unable to eradicate transformed cells. First, tumor cells are derived from host cells and resemble normal cells in many respects. Therefore, most tumors tend to be weakly immunogenic. Tumors that elicit strong immune responses include those induced by oncogenic viruses, in which the viral proteins are foreign antigens. Second, the rapid growth and spread of tumors may overwhelm the capacity of the immune system to effectively control a tumor, which requires that all the malignant cells be eliminated. Third, many tumors have specialized mechanisms for evading host immune res

9. TUMOR ANTIGENS A variety of tumor antigens that may be recognized by T and B lymphocytes have been identified in human and animal cancers. In the experimental situation, as in MCA-induced mouse sarcomas, it is often possible to demonstrate that these antigens elicit adaptive immune responses and are the targets of such responses. 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 dysregulated in tumors.

10. IMMUNE RESPONSES TO TUMORS The effector mechanisms of both innate and adaptive immunity have been shown to kill tumor cells Innate Immune Responses to Tumors Some of the early research on functions of effector cells of the innate immune system, including NK cells and macrophages, focused on the ability of these cells to kill cultured tumor cells.

11. NK Cells 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. In vitro, NK cells can kill virally infected cells and certain tumor cell lines, especially hematopoietic tumors. NK cells also respond to the absence of class I MHC molecules because the recognition of class I MHC molecules delivers inhibitory signals to NK cells

12. Macrophages Macrophages are capable of both inhibiting and promoting the growth and spread of cancers, depending on their activation state. Classically activated M1 macrophages, display various anti-tumor functions. These cells 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 IFN-γ produced by tumor-specific T cells. M1 macrophages can kill tumor cells by several mechanisms, probably the same as the mechanisms of macrophage killing of infectious organisms. These include the release of lysosomal enzymes, reactive oxygen species, and nitric oxide.

13. M1 macrophages also produce the cytokine tumor necrosis factor (TNF), which was first characterized, as its name implies, as an agent that can kill tumors. We now know it does so mainly by inducing thrombosis in tumor blood vessels. In contrast, M2 macrophages may contribute to tumor progression . These cells secrete vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and other soluble factors that promote tumor angiogenesis.

14. Adaptive Immune Responses to Tumors Tumors elicit both T cell–mediated and humoral immune responses. T cells are the principal mediators of antitumor immunity, and this realization has led to considerable efforts to enhance T cell responses for the immunotherapy of cancers

15. T Lymphocytes The principal mechanism of adaptive tumor immunity is killing of tumor cells by CD8+ CTLs. The ability of CTLs to provide effective anti-tumor immunity in vivo is most clearly seen in animal experiments using carcinogen induced and DNA virus–induced tumors. 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

16. 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 effective CTL development. 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. IFN-γ may also activate macrophages to kill tumor cells. The importance of IFN-γ in tumor immunity is demonstrated by the finding of increased incidence of tumors in knockout mice lacking this cytokine, the IFN-γ receptor, or components of the IFN-γ receptor signaling cascade.

17. Antibodies 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. Some effective therapeutic anti-tumor antibodies that are passively administered to patients likely work by antibody-dependent cell mediated cytotoxicity.

18. 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 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

19. Intrinsic Mechanisms of Immune Evasion by Tumor Cells Several properties of tumor cells enable them to escape host defenses. Tumors may lose expression of antigens that elicit immune responses. Such “ antigen loss variants ” are common in rapidly growing tumors and can readily be induced in tumor cell lines by culture with tumor specific antibodies or CTLs. 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 have a growth advantage in the host. Analysis of tumors that are serially transplanted from one animal to another has shown that the loss of antigens recognized by tumor-specific CTLs correlates with increased growth and metastatic potential.

20. Apart from tumor-specific antigens, class I MHC expression may be downregulated 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.

21. Tumor antigens may be inaccessible to the immune system . The cell surface antigens of tumors may be hidden from the immune system by glycocalyx molecules, such as sialic acid–containing mucopolysaccharides. This process is called antigen masking and may be a consequence of the fact that tumor cells often express more of these glycocalyx molecules than normal cells do.

22. Tumors may fail to induce strong effector T cell responses because most tumor cells do not express costimulators or class II MHC molecule . Costimulators are required for initiation of T cell responses, and class II molecules are needed for the activation of helper T cells, which in some circumstances are required for the differentiation of CTLs . Therefore, the induction of tumor-specific T cell responses often requires cross-priming by dendritic cells , which do express costimulators and class II molecules. If such APCs do not adequately take up and present tumor antigens and activate helper T cells, CTLs specific for the tumor cells may not develop.

23. Tumors may engage molecules that inhibit immune responses . There is good experimental evidence that T cell responses to some tumors are inhibited by the involvement of CTLA-4 or PD-1 A possible reason for this role of CTLA-4 is that tumor antigens are presented by APCs in the absence of strong innate immunity and thus with low levels of B7 costimulators . These low levels may be enough to engage the high-affinity receptor CTLA-4. PD-L1, a B7 family protein that binds to the T cell inhibitory receptor PD-1 is expressed on many human tumors, and animal studies indicate that antitumor T cell responses are compromised by PD-L1 expression

24. PD-L1 on APCs may also be involved in inhibiting tumor-specific T cell activation. there are ongoing clinical trials of blockade of the CTLA-4 and PD-L1/PD-1 pathways to enhance tumor immunity. Some tumors express Fas ligand ( FasL ), which recognizes the death receptor Fas on leukocytes that attempt to attack the tumor; engagement of Fas by FasL may result in apoptotic death of the leukocytes.

25. Secreted products of tumor cells may suppress anti-tumor immune responses . An example of an immunosuppressive tumor product is TGF-β, which is secreted in large quantities by many tumors and inhibits the proliferation and effector functions of lymphocytes and macrophage

26. Extrinsic Cellular Suppression of Anti-Tumor Immunity Several cell populations have been described in tumor bearing patients and animals that suppress anti-tumor immunity.

27. Tumor-associated macrophages may promote tumor growth and invasiveness by altering the tissue microenvironment and by suppressing T cell responses . These macrophages have an M2 phenotype, and they secrete mediators, such as IL-10, prostaglandin E2, and arginase, that impair T cell activation and effector functions. Tumor-associated macrophages also secrete factors that promote angiogenesis , such as TGF-β and VEGF, which enhances tumor growth.

28. Regulatory T cells may suppress T cell responses to tumors . Evidence from mouse model systems and cancer patients indicates that the numbers of regulatory T cells are increased in tumor-bearing individuals, and these cells can be found in the cellular infiltrates in certain tumors. Depletion of regulatory T cells in tumor-bearing mice enhances anti-tumor immunity and reduces tumor growth.

29. 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

30. 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 severe effects on normal proliferating cells. As a result, the treatment of cancers causes significant morbidity and mortality

31. Immune responses to tumors may be specific for tumor antigens and will not injure most 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 .

32. Stimulation of Active Host Immune Responses to Tumors The earliest attempts to boost anti-tumor immunity relied on nonspecific immune stimulation. More recently, vaccines composed of killed tumor cells, tumor antigens, or dendritic cells incubated with tumor antigens have been administered to patients, and strategies to enhance immune responses against the tumor are being developed.

33. Vaccination with Tumor Antigens Immunization of tumor-bearing individuals with tumor antigens may result in enhanced immune responses against the tumor

34. Augmentation of Host Immunity to Tumors with Costimulators and Cytokines Cell-mediated immunity to tumors may be enhanced by expressing costimulators and cytokines in tumor cells and by treating tumor-bearing individuals with cytokines that stimulate the proliferation and differentiation of T lymphocytes and NK cells.

35. Blocking Inhibitory Pathways to Promote Tumor Immunity Another immunotherapeutic strategy is based on the idea that tumor cells exploit various normal pathways of immune regulation or tolerance to evade the host immune response. One series of studies in mice and humans has targeted the inhibitory receptor for B7, CTLA-4, which functions normally to shut off responses against self antigens Combination therapy with a tumor vaccine and an antibody that blocks CTLA-4 induces a strong anti-tumor T-cell response that destroys the tumor. Anti–CTLA-4 antibody has been used with some success in clinical trials with patients with advanced tumors. A common complication of this treatment has been the development of autoimmune reactions, which is predictable in light of the known role of CTLA-4 in maintaining self-tolerance. T cell responses against tumors may also be inhibited by the PD-L1/PD-1 pathway. Antibody blockade of PD-1 is effective in enhancing T cell killing of tumors in mice, and human clinical trials using this approach are under way.

36. Nonspecific Stimulation of the Immune System Immune responses to tumors may be stimulated by the local administration of inflammatory substances or by systemic treatment with agents that function as polyclonal activators of lymphocytes . Nonspecific immune stimulation of patients with tumors by injection of inflammatory substances such as bacillus CalmetteGuérin (BCG) at the sites of tumor growth has been tried for many years.

37. Passive Immunotherapy for Tumors with T Cells and Antibodies Passive immunotherapy involves the transfer of immune effectors, including tumor-specific T cells and antibodies, into patients. Passive immunization against tumors is rapid but does not lead to long-lived immunity. Some anti-tumor antibodies are now approved for the treatment of certain cancers .

38. Adoptive Cellular Therapy Adoptive cellular immunotherapy is the transfer of cultured immune cells that have anti-tumor reactivity into a tumor-bearing host. The cells to be transferred are expanded from the lymphocytes of patients with the tumor

39. Therapy with Anti-Tumor Antibodies Tumor-specific monoclonal antibodies may be useful for specific immunotherapy for tumors Currently, there are more than 100 different monoclonal antibodies being considered, either in experimental animal studies or in human trials, as therapeutic agents for cancer, and a few have been approved for clinical use Anti-tumor antibodies may eradicate tumors by the same effector mechanisms that are used to eliminate microbes, including opsonization and phagocytosis, activation of the complement system, and antibody-dependent cellular cytotoxicity . These mechanisms are likely at work in B cell lymphoma patients treated with anti-CD20 ( rituximab) , one of the most successful anti-tumor antibody treatments to date

40. THE ROLE OF THE IMMUNE SYSTEM IN PROMOTING TUMOR GROWTH Although much of the emphasis in tumor immunology has been on the role of the immune system in eradicating tumors, it is clear that the immune system may also contribute to the development of some solid tumors. In fact, chronic inflammation has long been recognized as a risk factor for development of tumors in many different tissues, especially those affected by chronic inflammatory diseases such as Barrett’s esophagus, Crohn’s disease, pancreatitis, and prostatitis, for example. Some cancers associated with infections are also considered to be an indirect result of the carcinogenic effects of the chronic inflammatory states that are induced by the infectious organisms. These include gastric cancer in the setting of chronic Helicobacter pylori infection and hepatocellular carcinomas associated with chronic hepatitis B and C virus infection