Immunity to Tumors

Immunty & Cancer Cancer is a major health problem worldwide and one of the most important causes of morbidity and mortality in children and adults. According to the concept of immune surveillance, proposed by Macfarlane Burnet in the 1950s, 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.

تومور (Tumor) يا Neoplasm: Tumor = Swelling (Latin) تومور ناشی از تغییر در ژنوم سلولهاست که موجب تکثیر کنترل نشده و نا محدود آنها و تهاجم آنها به بافت های نرمال می شود. اشعه ها، برخی مواد شیمیایی و برخی ویروس ها سبب ایجاد Transformation در سلولها و سرطانی شدن آنها می شوند. Benign tumor (خوش خيم) Malignant tumor (بد خيم)

General features of Tumor Immunity Tumors stimulate specific immune responses. Immune response Frequently fail to prevent Tumor growth. The immune system can be activated by external stimuli to effectively kill tumor cells and eradicate tumors.

Experimental demonstration of tumor immunity

Tumor Antigen Tumor Specific Transplantation Antigen (TSTA): Only Express on tumor cells. Tumor-Associated Transplantation Antigen (TATA) : In addition to tumor cells, express during fetal life, and or in low concentration in normal cells. The modern classification of tumor antigens is based on the molecular structure and source of antigens expressed by tumor cells.

Identification of Tumor Antigens

Identification of Ab specific Tumor Ag A successful method for identification of tumor antigens that have stimulated humoral immune responses in tumor patients is called the serologic analysis of recombinant cDNA expression (SEREX). In this method, libraries of cDNA derived from a patient’s tumor RNA are transfected into a cell line, and assays are performed to detect binding of the cancer patient’s serum immunoglobulins to the transfected cells.

Tumor Antigens

Tumor Antigen a) Products of Mutated Oncogenes & Tumor Suppressor: Products of Mutated Genes: a) Products of Mutated Oncogenes & Tumor Suppressor: - Oncogenes (neu, abl, ras و myc) - Tumor suppressor (Retinoblastoma (Rb) & P53) b) Products of Randomly mutated genes : - Tumor antigens may be produced by randomly mutated genes (by chemical carcinogen or radiation) whose products are not related to the malignant phenotype.

2. Abnormally Expressed Cellular Proteins: Tyrosinase: an enzyme involved in melanin biosynthesis that is expressed only in normal melanocytes and melanoma. - Cancer/testis Ags: MAGE Ag expressed in bladder, breast, skin, lung, prostate carcinoma and some sarcomas, as well as in normal testes.

3. Antigens of Oncogenic Viruses: - DNA Viruses: EBV (B cell lymphomas and nasopharyngeal carcinoma) and HPV (associated with cervical carcinoma). SV40 & Polyoma virus - RNA Viruses: HTLV-1 - All tumors induced by the same type of virus have the same Ags.

4. Oncofetal Antigens: - Oncofetal Ags are proteins that are expressed at high Levels in cancer cells and in normal developing fetal but not adult tissues. - : CEA يك پروتئين غشايي كه زمان جنيني در روده و پانكراس و كبد عرضه مي شود، اما در كارسينوم كولون، معده، پانكراس و پستان سطح سرمي آن افزايش مي يابد. - AFP : يك پروتئين محلول كه توسط كبد و كيسه زرده در زمان جنيني توليد مي شود. سطح سرمي آن در كارسينوم كبد، و معده و پانكراس افزايش مي يابد.

5. Altered Glycolipid and Glycoprotein Ags: (diagnostic markers & target for therapy) - Gangliosides: GM2, GD2, and GD3 are expressed at high levels in neuroblastomas, melanomas & many sarcomas. - Mucins: CA-125 and CA-19-9, expressed on ovarian carcinomas, and MUC-1, expressed on breast carcinomas.

(Target for therapy & tumor origin identification) 6. Tissue-Specific Differentiation Antigens: (Target for therapy & tumor origin identification) - CD10 (common acute lymphoblastic leukemia antigen, or CALLA) and CD20 are diagnostic marker of B cell ALL.

Immune Response to tumor

Macrophages (MΦ) MΦ possibly activated by direct recognition of some surface antigens of tumor cells and by IFN-γ produced by tumor-specific T cells. Activated MΦ exhibit selective cytotoxicity against tumor cells. M1 but not M2 MΦ kill by releasing lysosomal enzymes, reactive oxygen, nitric oxide or secretion of TNF.

NK Cells NK kill many types of tumor cells, that have reduced class I MHC expression and express ligands for NK cell activating receptors. Some Tumors express MICA, MICB & ULB which are bind to NKG2D on NK cell.

CTL response to Tumor The principal mechanism of adaptive immune protection against tumors is killing of tumor cells by CD8+ CTLs.

Mechanisms of Tumor escape

Intrinsic Mechanisms of Immune vasion by Tumor Cells Tumors may lose expression of Ags that elicit immune responses. Tumor Ags may be inaccessible to the immune system. By masking with glicocalyx molecules. Tumors cells do not express costimulators or class II MHC molecules. Tumors may engage molecules that inhibit immune responses: CTLA-4 or PD-L1 Tumor cells products may suppress anti-tumor immune responses: TGF-β

Extrinsic Cellular Suppression of Anti-Tumor Immunity Tumor-associated MØ (M2): may promote tumor growth and invasiveness by altering the tissue microenvironment and by suppressing T cell responses by secreting: IL-10, PGE2 , and arginase. Regulatory T cells: may suppress T cell responses to tumors. Myeloid-derived suppressor cells (MDSCs): are immature myeloid precursors that accumulate in lymphoid tissues, blood, or tumors of cancer patients and suppress anti-tumor innate and T cell responses. They secret: IL10, arginase, NO synthase & induce Treg & TH2.

Tumor Immunotrapy Active immunotherapy Passive immunotherapy specific Nonspecific Passive immunotherapy Specific

Tumor Vaccine

Enhancement of Immunogenicity by costimulator & Cytokine genes

Systemic Cytokine Therapy for Tumor

Blocking inhibitory molecule - Using anti-CTLA-4 - Using anti-PD-1 Nonspecific Stimulation of Immune system - Using BCG - anti-CD3

T cell inhibitor blockade

Passive Immunotherapy Adoptive cellular immunotherapy Isolate lymphocytes from blood or tumor infiltrate Expand lymphocytes by culture in IL-2  lymphokine-activated killer (LAK) cells Transfer LAK cells into patient, with or without systemic IL-2. Graft-Versus-Leukemia Effect: - In leukemia patients, administration of alloreactive T cells together with stem cell can contribute to eradication of the tumor.

Adoptive cellular immunotherapy

Therapy with Anti-Tumor Antibodies Tumor-specific monoclonal antibodies may be useful for specific immunotherapy for tumors.

Antibodies

Passive Specific Immunotherapy