Cancer Immunology PDF

Cancer Immunology Dr Sherko Ali Omer Dept. of Basic Medical Sciences Learning objectives By the end of the session students should be able to: Define tumor antigens including tumor-specific transplantation antigens, tumor-associated transplantation antigens, and tumor markers. Understand immune resp...

Cancer Immunology Dr Sherko Ali Omer Dept. of Basic Medical Sciences Learning objectives By the end of the session students should be able to: Define tumor antigens including tumor-specific transplantation antigens, tumor-associated transplantation antigens, and tumor markers. Understand immune response against tumor cells and the elements of such response. Explain immune surveillance, immune evasion by tumor cells. Identify cancer immunotherapy, cell-based therapies, monoclonal antibodies, cytokine therapies and cancer vaccines. 2 Tumors Tumor cells can be viewed as altered self-cells that have escaped normal growth-regulating mechanisms. Tumour immunology is concerned with the unique properties of cancer cells, paying particular attention to those properties that can be recognized by the immune system, the immune responses that develop to cancer cells and immunotherapies for cancer. 3 Tumors Tumour or neoplasm are cells that give rise to progeny with the ability to expand in an uncontrolled manner. Benign tumours are not capable of indefinite growth and does not invade the healthy surrounding tissue while malignant tumours continue to grow and becomes progressively more invasive. Cancer refers specifically to a malignant tumour. 4 Tumors Most malignant tumors eventually exhibit metastasis, whereby small clusters of cancerous cells dislodge from the original tumor, invade the blood or lymphatic vessels, and are carried to distant sites where they take up residence and continue to proliferate. In this way, a primary tumor at one site can give rise to a secondary tumor at another site. 5 Tumors Normal cells can be transformed in vitro by chemical and physical carcinogens and by transforming viruses. Transformed cells exhibit altered growth properties and are sometimes capable of inducing cancer when they are injected into animals. Proto-oncogenes encode proteins involved in control of normal cellular growth and division. The conversion of proto-oncogenes to oncogenes is one of the key steps in the induction of most human cancer. 6 Tumors This conversion may result from mutation in an oncogene, its translocation, or its amplification. A number of B- and T-cell leukemias and lymphomas are associated with translocated proto-oncogenes. In its new site, the translocated gene may come under the influence of enhancers or promoters that cause its transcription at higher levels than usual. 7 Response to tumors The immune response to tumors consists of a number of wellorchestrated steps that ultimately lead to tumor recognition, targeting, and killing. This process was termed the cancer immunity cycle by Chen and Mellman in 2013. While many different cell types are involved in this process, T cells and DCs play central roles in the anticancer response. The cancer immunity cycle consists of seven steps that lead to a selfrenewing process. 8 Cancer immunity cycle (MHC-I, major histocompatibility complex I; TCR, T-cell receptor). (Adapted from Chen, D., Mellman, I., Immunity, 39, 1–13, 2013.) 9 Response to tumors The cancer cycle consist from: 1. 2. 3. 4. 5. 6. 7. Tumor cell antigen release Antigen presentation by dendritic cells Priming and activation of tumor- specific T lymphocytes Trafficking to tumor site Infiltration into tumor tissue Recognition of tumor cells Killing of tumor cells 10 Tumor antigens In the course of neoplastic transformation, new antigens (neoantigens) called tumor-associated antigens (TAAs), develop at the cell surface, and the host recognizes such cells as “nonself.” An immune response then causes the tumor to regress. Two types of tumor antigens have been identified on tumor cells: Tumor-specific transplantation antigens (TSTAs) or TSAs Tumor-associated transplantation antigens (TATAs) TAAs 11 Tumor antigens https://blog.crownbio.com/tumor-antigens-t-cell-therapy 12 Tumor-Specific Transplantation Antigens (TSTAs) Tumor-specific antigens are highly specific; cells of one tumor will have different TSTAs from the cells of another tumor. They arise from mutations in tumor cells that generate altered cellular proteins. Cytosolic processing of these proteins would give rise to novel peptides that are presented with class I MHC molecules, to induce a cell-mediated immune response by tumor-specific cytotoxic T lymphocytes. TSTA are induced on tumor cells either by physical (UV) carcinogens or by chemical (Methylcholanthrene), and also by viral carcinogens. 13 Tumour-Specific Transplantation Antigens (TSTAs) In contrast, the TSTA of virus induced tumours is virus specific; all tumours produced by one virus would possess the same antigen. Example: Epstein Barr virus which causes nasopharyngeal carcinoma and several types of lymphoma. 14 Tumor-Associated Transplantation Antigens (TATAs) These TATSs are not unique to tumor cells and may also be expressed by normal cells but at a very low level, but their level gets exponentially high in tumor cells. Oncofetal antigens- proteins that are expressed on normal cells during fetal life but not expressed in the adult normally. Reactivation of the embryonic genes that encode these proteins in tumor cells results in their expression on the fully differentiated tumor cells; examples include alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA). 15 Tumor-Associated Transplantation Antigens (TATAs) Non-oncofetal TATAs: Examples include Carbohydrate Antigens (CA 125, CA 19-9), prostate specific antigen (PSA) and Beta-2 microglobulin. MUC1 is a heavily glycosylated trans-membrane protein that is expressed on the apical surface of glandular epithelial cells. In tumor cells, MUC1 is overexpressed, underglycosylated, and its expression is no longer limited to the apical surface of cells. These changes in the expression pattern lead to generation of tumor-associated MUC1 antigens that are immunogenic. 16 TATAs used as tumor markers for diagnosis of cancers Tumor markers Oncofetal proteins Alpha-fetoprotein (AFP) Carcinoembryonic antigen (CEA) Secreted tumor antigens CA 125 CA 19-9 Prostate-specific antigen β 2 microglobulin Hormones β subunit of chorionic gonadotropin Tumor types Hepatoma Testicular cancer Gastrointestinal cancers Lung, ovarian cancers Ovarian cancers; Other epithelial cancers Various carcinomas Prostate cancer Multiple myeloma Hydatidiform mole choriocarcinoma; Testicular cancers 17 Immune response against tumor cells After TATAs or TSTAs are released into the tumor microenvironment, they are taken up by DCs. Tumor antigens are processed and presented by DCs on classI and class-II MHC molecules. As these antigens are being processed, DCs traffic to lymph nodes where they will be presented to T cells. 18 Immune response against tumor cells The nature of the costimulatory signals determines whether an effective antitumor T-cell response will be elicited or whether regulatory T cells will be generated resulting in the development of tolerance. In general, the optimal anti-cancer T cell response should include a combination of effector CD8+ T cells and helper CD4+ T cells. 19 Immune response against tumor cells DCs coordinate CD4 and CD8 T cell anti-tumor immune responses. 20 Immune response against tumor cells Both humoral and cell-mediated immune responses are induced by tumor antigens that result in the destruction of the tumor cells. Cell-mediated response appears to play the major role: § Cytotoxic T (CD8+) cells § NK cells § Activated macrophages, which rely on antigen-specific Th-1 cells and cytokines for activation. o 21 Immune response against tumor cells Tumor antigens can stimulate the development of specific antibodies as well. Some of these antibodies are cytotoxic, but others, called blocking antibodies, can actually enhance tumor growth. This might be due to blocking recognition of tumor antigens by the host or due to binding of the Fc regions to inhibitory Fc receptors. 22 Cytotoxic T cells Number of tumors have been shown to induce tumorspecific TC cells (CD8+) that recognize tumor antigens presented by class I MHC on the tumor cells. Expression of class I MHC molecules are decreased in a number of tumors, thereby limiting the role of specific TC cells in their destruction. 23 NK cells Natural killer recognition of tumor cells is not MHC restricted. Activity of NK cells is not compromised; but enhanced by the decreased MHC expression exhibited by some tumor cells. The inhibitory receptors of NK cells will be no longer functional in the absence of MHC I molecules on the target cells so that the activation receptors become active. 24 NK cells The activation or lack of activation of cytotoxic pathways depends on the balance between activating receptors (NKAR) which interacts with cellular glycoproteins and inhibitory receptors (NKIR) which interacts with self MHC-I molecules. 25 NK cells If the inhibitory receptor is not triggered (due to either lack of interaction of the inhibitory receptor with MHC 1 peptide complex, or to downregulation of expression of MHC I molecules on the cell membrane), stimulatory activity prevails, and the target cell is killed. Overexpression of modified cellular glycoproteins (in malignant cells of viral-infected cells) can cause a very strong activating signal, able to override the downregulating signal mediated by MHC-I recognition. 26 NK cells Activation receptors can be Fc receptors on NK cells which can bind to antibody-coated tumor cells, leading to ADCC. The importance of NK cells in tumor immunity is suggested by the mutant mouse strain called beige and Chediak-Higashi syndrome in humans. In each case, a genetic defect causes marked impairment of NK cells and an associated increase in certain types of cancer. 27 Immune surveillance theory The immunological surveillance hypothesis states that tumors arise with similar frequency to infection with pathogens and that the immune system constantly recognizes and rejects these tumors on the basis of the expression of foreign TAAs. The presence of TAAs was based on the finding that tumors induced in animal models were frequently rejected when transplanted into syngeneic hosts, whereas transplants of normal tissues between syngeneic hosts were accepted. 28 Immune evasion by tumor cells VEGT :Vascular endothelia growth factor; PD: programmed death ligand 1 (PD-L1); CTLA4:T lymphocyte–associated molecule 4 29 Immune evasion by tumor cells Anti-tumor antibodies produced against tumor antigens may have a role in immune evasion. Blocking factor-antitumor antibody may act as a blocking factor. The antibody binds to tumor-specific antigen and masks the antigen from cytotoxic T cells and NK cells. Antigenic modulation-Certain tumor-specific antigens have been observed to disappear from the surface of tumor cells in the presence of serum antibodies and then to reappear after disappearance of serum antibodies. 30 Immune evasion by tumor cells Masking the immune cells- Circulating tumour antigens may act as a 'smokescreen', coating the lymphoid cells and preventing them from acting on the tumour cells. 31 Immune evasion by tumor cells Expressing low levels of MHC I- Many tumor cells down regulate the expression of MHC I molecules; hence preventing their recognition by cytotoxic T cells (what about NK cells!) Poor co-stimulatory signals-The co-stimulatory signal of T cell activation is provided by interaction between the CD28 molecules on T cell surface with the B7 molecules on the APCs. The poor immunogenicity of many tumor cells may be due to lack of the costimulatory molecules on APCs. 32 Immune evasion by tumor cells Secrete soluble factors- Certain tumor cells secrete soluble factors such as IL-10 and TGF-β that may suppress the immune responses against the tumor cells. Expressing Fas ligand-Some tumor cells express Fas ligand on their surface, which when interact with Fas (the death receptor) on T cells, causes apoptosis of T cells. Increased opportunistic infections- Patients with advanced cancers have an increased susceptibility to various opportunistic infections which in turn depresses the T cell responses. 33 Cancer immunotherapy Harnessing the power of the immune system to target and destroy cancer has been the central goal of tumor immunologists for decades. Along with chemotherapy, surgery, and radiation, immunotherapy is now becoming the fourth pillar of treatment for many malignancies. 34 Cancer immunotherapy, adoptive cell therapy Adoptive cell therapy (ACT) involves the isolation, ex vivo manipulation, and reinfusion of T cells into cancer patients in order to treat their disease. The initial purpose behind ACT was to isolate T cells and expand them ex vivo in order to circumvent the immunosuppressive mechanisms present in cancer patients. 35 Cancer immunotherapy, adoptive cell therapy 36 Monoclonal Antibodies Monoclonal antibodies (MAbs) have become an integral part of cancer therapy. MAbs target surface proteins on tumor cells and can lead to tumor destruction by a number of ways: 1. Direct cytotoxicity by activating the complement system leading to tumor cells lysis 2. Induction of ADCC 37 Monoclonal Antibodies 3. Binding to stimulatory receptors that can activate signaling pathways leading to growth arrest and death, or 4. Binding to growth factors or their receptors and blocking the positive effect of those growth factors on tumor cells. 38 Monoclonal Antibodies Monoclonal antibodies Target Approved for treatment of cancers Alemtuzumab CD52 Chronic lymphocytic leukaemia (CLL) Bevacizumab Vascular endothelia growth factor Colorectal, lung and renal cancer Cetuximab Colorectal, the head and neck cancer Ipilimumab Rituximab Tositumomab Epidermal growth factor receptor CTLA4 CD20 CD20 Trastuzumab ErbB2 Breast cancer Metastatic melanoma CLL Non-Hodgkin lymphoma 39 Cytokine Therapies Cytokines regulate and coordinate the behavior of the immune system. Examples of cytokine include: Interferon-α is used in the treatment of hairy-cell leukemia, AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukemia and malignant melanoma. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma. 40 Cancer immunotherapy, cell-based therapies (cancer vaccines) Cell types that can be used in cancer vaccines include NK cells, cytotoxic T cells and dendritic cells. Only cell-based therapy currently approved for use is dendritic cells (Provenge) for the treatment of prostate cancer. 41 Cancer Vaccines Preventive cancer vaccines: Example - HPV and hepatitis B vaccine, these prevent the emergence cervical and liver cancers respectively. Therapeutic cancer vaccines: Used to treat existing cancers. Research is ongoing for preparation of such vaccines. Vaccines against some oncogenic viruses have proven extremely effective. 42 Reference Medical Immunology, 7th Edition, edited by Gabriel Virella, CRC Press LLC, 2019 43 Thanks! 44