IMMUNE RESPONSE TO TUMORS

IMMUNE RESPONSE TO TUMORS-Humoral immunity
-Cellular Immunity- Failure of Host Defenses
- Evasion of Immune Responses by Tumors
- Cancer Immunosurveillance vs Immunoediting- Immunotherapy

1. IMMUNE RESPONSE TO TUMORS Ms Saajida Sultaana Mahusook

2. The immune response to cancer can be viewed as a specialised case of immunity in which the malignant cell has adapted and learned how to persist . Burnet and Thomas put forth the immunological surveillance theory as the immune system continually surveyed the body for the presence of malignant cells, which were continuously arising as a result of mutations . Potential strength of immune surveillance is based on the knowledge that cancer cells express tumour-associated antigens (TAAs) or tumour-specific antigens (TSAs) that can be recognised by the immune system as foreign elements . Development of cancer can be explained by the ability of tumour cells to evade immune recognition either by the failure of the immune system or by the induction of immune tolerance or other inhibitory mechanisms that allows tumour to escape immune detection and elimination.

3. The immune response to foreign antigens consists of Humoral mechanisms ( eg , antibodies) Cellular mechanisms Most humoral responses cannot prevent tumor growth. E ffector cells, such as T cells, macrophages, and NK cells, have relatively effective tumoricidal abilities. Effector cell activity is induced by cells that present tumor -specific antigens (TSAs) or tumor -associated antigens (TAAs) on their surface (these cells are called antigen-presenting cells) and is supported by  cytokines (such as interleukins, interferons ). Despite the activity of effector cells, host immunoreactivity may fail to control tumor occurrence and growth .

4. Humoral immunity Humoral antibodies do not appear to confer significant protection against tumor growth. Most antibodies cannot recognize TAAs. Humoral antibodies that react with tumor cells in vitro have been detected in the sera of patients with various tumors , such as Burkitts lymphoma, melanoma, osteosarcoma, neuroblastoma , lund and breast carcinomas. Cytotoxic antibodies are directed against surface antigens of tumor cells. These antibodies can exert anti- tumor effects through complement fixation or by serving as a flag for destruction of tumor cells by T cells (antibody-dependent cell-mediated cytotoxicity). Another population of humoral antibodies, called enhancing antibodies (blocking antibodies), may actually favor rather than inhibit tumor growth.

5. Cellular Immunity The T cell is the primary cell responsible for direct recognition and killing of tumor cells. T cells carry out immunologic surveillance, proliferate and destroy newly transformed tumor cells after recognizing TAAs. Some cells require the presence of humoral antibodies directed against the tumor cells (antibody-dependent cellular cytotoxicity) to kill tumor cells. In contrast, suppressor T cells inhibit the immune response against tumors . Cytotoxic T lymphocytes   ( CTLs) recognize antigens on target cells and lyse these cells. These antigens may be cell surface proteins or may be intracellular proteins ( eg , TAAs) that are expressed on the surface in combination with class I major histocompatibility complex (MHC) molecules. Tumor -specific CTLs have been found in Sarcomas , carcinomas(lung, breast, cervical,colon ), malanomas .

6. Natural killer (NK) cells   NK cells are effector cells with tumoricidal activity. NK cells lack the receptor for antigen detection but can recognize normal cells infected with viruses or tumor cells. Their tumoricidal activity is termed natural because it is not induced by a specific antigen. Evidence suggests that class I MHC molecules on the surface of normal cells inhibit NK cells and prevent lysis . Thus , the decreased level of class I molecule expression characteristic of many tumor cells may allow activation of NK cells and subsequent tumor lysis .

7. Macrophages   Macrophages  can kill specific tumor cells when activated by a combination of factors, including lymphokines (soluble factors produced by T cells) and interferon. They are less effective than T-cell–mediated cytotoxic mechanisms. Under certain circumstances, macrophages may present TAAs to T cells and stimulate tumor -specific immune response. There are at least 2 classes of tumor -associated macrophages (TAM): TAM-1 (M1) cells facilitate T cell killing of tumors TAM-2 (M2) cells promote tumor tolerance M1 and M2 are considered to exist on a continuum until they maximally differentiate (polarize) into M1 and M2. Such polarization can vary over time and depends on the stage and type of cancer as well as treatments.

8. Dendritic cells   Dendritic cells  are dedicated antigen-presenting cells present in barrier tissues (such as skin, lymph nodes). They play a central role in initiation of tumor -specific immune response. These cells take up tumor -associated proteins, process them, and present TAAs to T cells to stimulate the CTL response against tumor . Several classes of dendritic cells can mediate tumor promotion or suppression . Lymphokines   Lymphokines produced by immune cells stimulate growth or induce activities of other immune cells . Such lymphokines include interleukin-2 (IL-2), also known as T-cell growth factor, and the interferons . IL-12 is produced by dendritic cells and specifically induces CTLs, thereby enhancing antitumor immune responses.

9. Regulatory T cells   T reg cells are normally present in the body and help prevent autoimmune reactions. They are produced during the active phase of immune responses to pathogens and limit the strong immune response that could damage the host. Accumulation of these cells in cancers inhibits antitumor immune responses . Myeloid-derived suppressor cells   Myeloid-derived suppressor cells consist of immature myeloid cells and their precursors. These cells increase in number in cancer, inflammation and infection. The cells have potent immune suppressive activity. Two populations of these cells are recognized: Granulocytic Monocytic Myeloid-derived suppressor cells accumulate in large numbers in cancers and predict poor clinical outcomes in various types of cancer.

10. Role of the Adaptive Immune System in Tumour Immunity: Recognition of TAAs on Tumour Cells by T Cells and Other Cells

11. Failure of Host Defenses Although many tumors are eliminated by the immune system, others continue to grow despite the presence of TAAs. Several mechanisms have been proposed to explain this deficient host response to the TAA, including the following : Specific immunologic tolerance to TAAs in a process that involves APC’s and suppressor T cells, possibly secondary to prenatal exposure to the antigen Suppression of immune response by chemical, physical, or viral agents ( eg , helper T-cell destruction by HIV ) Suppression of the immune response by cytotoxic drugs or radiation Suppression of the immune response by the tumor itself through various complex and largely uncharacterized mechanisms that cause various problems including decreased T, B, APC function , decreased IL-2 production, and increased circulating soluble IL-2 receptors (which bind and hence inactivate IL-2 ) Presence and activity of TAM-2 (M2) polarized cells, promoting tumor tolerance

12. 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. Understanding the immune evasion mechanisms of tumors , is important to prevent immune evasion that will increase the immunogenicity of tumors and maximize the responses of the host . Escaping Immune Recognition by Loss of Antigen Expression Active Inhibition of Immune Responses

13. 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, by a process 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 .

14. 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.

15. 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.

16. Cancer Immunosurveillance vs Immunoediting Cancer immunoediting process consists of three phases: Elimination Equilibrium Escape Elimination phase corresponds to the concept of cancer immunosurveillance , whereby nascent tumour cells are successfully recognised and eliminated by the immune system, thus returning the tissues to their normal state of function . Tumour cells that elude the immunosurveillance phase will progress to the immune editing phase, called the equilibrium phase of advanced oncogenesis , where tumour expansion and metastasis are minimal (tumour dormancy) and usually occur without symptoms.

17. In the equilibrium phase, the immune system may eventually eliminate all tumour cells leading to an outcome similar to the elimination phase. In a second scenario, the constant interaction of the immune system with tumours over a long period of time may actually “edit” or sculpt the phenotype of the developing tumour, resulting in the immunoselection of a tumour that has been shaped into a less-immunogenic state . Tumours that are no longer susceptible to immune attack then progress into the immunoediting process, termed “escape.” The emergence of clinical symptoms of cancer generally correlates with the escape stage . Tumour subverts the immune system, either directly through its nonimmunogenic phenotype, or indirectly through a variety of immunosuppressive mechanisms.

18. Immunotherapy Immunotherapy also called biologic therapy, is a type of cancer treatment that boosts the body's natural defenses to fight cancer. It uses substances made by the body or in a laboratory to improve or restore immune system function. Immunotherapy may work by: Stopping or slowing the growth of cancer cells Stopping cancer from spreading to other parts of the body Helping the immune system work better at destroying cancer cells

19. There are several types of immunotherapy, including : Monoclonal antibodies and tumor -agnostic therapies Non-specific immunotherapies Oncolytic virus therapy T-cell therapy Cancer vaccines

20. References: https://www.immunopaedia.org.za/immunology/special-focus-area/2-cancer-tumours/immune-responses-to-cancer / https:// www.msdmanuals.com/professional/hematology-and-oncology/tumor-immunology/host-response-to-tumors https:// www.omicsonline.org/immuno-defense-mechanism-against-tumors-1948-5956.S17-005.php?aid=3518 https:// www.creative-diagnostics.com/Tumor-Immunity.htm https:// academic.oup.com/annonc/article/23/suppl_8/viii6/185182 https:// www.cancer.net/navigating-cancer-care/how-cancer-treated/immunotherapy-and-vaccines/understanding-immunotherapy

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