Tumor Immunology Wirsma Arif Harahap Surgical Oncologist Surgery Department Andalas Medical School Wirsma Arif Harahap Surgical Oncologist Surgery Department Andalas Medical School

Immune System A complex of lymphoid organs highly specialized cells circulatory system separate from blood vessels A complex of lymphoid organs highly specialized cells circulatory system separate from blood vessels

Immune System Lymphatic vessels form a circulatory system that operates in close partnership with blood circulation Carries lymph, a fluid that contains WBCs (chiefly lymphocytes) Lymph nodes provide “meeting grounds” Lymphatic vessels form a circulatory system that operates in close partnership with blood circulation Carries lymph, a fluid that contains WBCs (chiefly lymphocytes) Lymph nodes provide “meeting grounds”

Four Primary Functions Recognition of self – self-tolerance – immunological privilege Immunosurveillance Intracellular hormones Defense against infection Recognition of self – self-tolerance – immunological privilege Immunosurveillance Intracellular hormones Defense against infection

Bacteria Tubercule bacillus StaphylococciFungi Candida albicans Virus Influenza Polio mellitus Parasites Tapeworms Malaria Helminths Role of the immune system is to protect from:

Eosinophil Monocyte Macrophage Neutrophil Basophil Origin of cells involved in the immune response Haemopoietic stem cell B cell Thymus NK cell Dendritic cell Mast cell Plasma cell CD4 T cell Myeloid progenitor Lymphocyte progenitor CD8 T cell

3 Types of Actions of the Immune System 1.Mechanical 2.Non-specific (innate immunity) 3.Specific ( adaptive immunity ) 1.Mechanical 2.Non-specific (innate immunity) 3.Specific ( adaptive immunity )

Overview of immune responses

Interactions between innate and & adaptive immunity 1. Innate immunity => Ag presentation (by Dendritic cells) 2. Adaptive immunity => Ag recognition (by T & B lymphocytes)

Evidence for the role of immune system in tumor rejection nSpontaneous regression nInfiltration of tumors by lymphocytes and macrophages nRegression of metastases after removal of primary tumor nRegression after chemotherapy nLymphocyte proliferation in draining lymph nodes nHigher incidence of cancer after immunosuppression/immunodeficiency (AIDS, neonates, aged, transplant patients)

Association between immunodeficiency and cancer  primary (inherited) immunodeficiency lymphomas Burkitt’s lymphoma  malaria  secondary (acquired) immunodeficiency lymphoma, cervical cancer, liver cancer, skin cancer, Kaposi’s sarcoma.  autoimmunitylymphoma malignancy cause of immuno- deficiency

Tumors stimulate an immune response  Animals can be immunized against tumors  Immunity is transferable from immune to naïve animals  Tumor specific antibodies and cell have been detected in humans with some malignancies  Animals can be immunized against tumors  Immunity is transferable from immune to naïve animals  Tumor specific antibodies and cell have been detected in humans with some malignancies

Etiology Of Tumor 1) Inherited : Expression of inherited oncogene e.g. viral gene incorporated into host gene 2) Viral: - Human papilloma, herpes type 2, HBV, EBV (DNA) - Human T-cell leuckemia virus (RNA) 3) Chemical: - Poly cyclic hydrocarbons cause sarcomas - Aromatic amines cause mammary carcinoma - Alkyl nitroso amines cause hepatoma 4) Radiological: Ultraviolet & ionizing irradiation 5) Spontaneous: failure in the cellular growth control

Tumor Associated Antigens !) Viral Antigen : a- Viral proteins and glycoproteins b- New antigens produced by virally infected host cells under control of viral nucleic acid 2) Tumor specific antigens : - Tumor cells develop new antigen specific to their carcinogens 3) Tumor specific transplantation antigens : - Tumor cells express new MHC antigens due to alteration of normally present MHC antigens

Tumor Associated Antigens 4) Oncofetal antigens: a- Carcino-embryonic antigens (CEA) - Normally expressed during fetal life on fetal gut - Reappearance in adult life: GIT, pancreas, biliary system and cancer breast b- Alpha fetoprotein: - Normally expressed in fetal life - Reappearance in adult life; hepatoma

Immunity against tumor All components, specific and nonspecific, humoral and cellular affect tumor progression and growth

Antigens expressed on tumor cells Major Histocompatability Complex antigens TSTA TATA TSTA : unique to a tumor Play an important role in tumor rejection. TATA : shared by normal and tumor cells Tumor-associated developmental Ag (TADA) Tumor-associated viral Ag (TAVA) TSTA : unique to a tumor Play an important role in tumor rejection. TATA : shared by normal and tumor cells Tumor-associated developmental Ag (TADA) Tumor-associated viral Ag (TAVA) Tumor-specific transplantation Ag Tumor-associated transplantation Ag

Tumor associated transplantation antigens : shared Ag on virally induced tumors

Discovery of tumor specific transplantation antigens, TSTA Discovery of tumor specific transplantation antigens, TSTA

Tumor-Associated Developmental Ags nFound on cancer cells and on fetal cells. nDo not trigger anti-tumor immunity. nUsed in diagnosis. uAlpha-fetoprotein(AFP) Cancers of liver uCarcinoembryonic Ag (CEA) colorectal cancer uBreast cancer  CA 15-3 uOvarial cancer  CA 15-5

Escape from immunosurveillance Lack of Neo-antigens

Escape from immunosurveillance Lack of Neo-antigens

Escape from immunosurveillance Lack of class I MHC

Escape from immunosurveillance Tumors secrete Immunosuppressive molecules

Escape from immunosurveillance Tumors shed their neo-antigens

Tumors escape the action of CTL by not expressing B7 which provides 2 nd signal involved in T cell activation tumor CTL tumor Ag Class I MHC B7 CD28 n Tumors may fail to express costimulatory molecules involved in T cell activation. molecules involved in T cell activation.

Utility of Immunology in Cancer Treatment

Use of tumor associated antigens  Raise monoclonal antibodies  Use antibodies for diagnosis  Use antibodies for therapy  Stimulate the in vivo specific response  Specific active treatment  Specific passive treatment  Adjuvant therapy to augment specific immunity  Raise monoclonal antibodies  Use antibodies for diagnosis  Use antibodies for therapy  Stimulate the in vivo specific response  Specific active treatment  Specific passive treatment  Adjuvant therapy to augment specific immunity

Use of tumor associated antigens monoclonal antibodies

Monoclonal antibodies: use as a diagnostic tool

Immunotherapy of tumors non- specific BCG, Propionibacterium acne, levamisole, etc. killed tumor cells, purified or recombinant Ag specific active immunotherapy LAK cells, cytokinesnon-specific antibodies alone or conjugated with other agent, activated T cells specific passive immunotherapy

Non-specific immunotherapy activate macrophages and NK cells IFN- , IFN- , IFN- , IL-2, TNF-  cytokines interferon productionpyran, poly I:C synthetic molecules activate macrophages and NK cells (via cytokines) BCG, P. acnes, muramyl dipeptide bacterial products

increased expression of class-I MHC, possible anti tumor effect remission of hairy cell leukemia, weak effect on carcinomas IFN increased expression of class-I MHC, Tc and NK cell activation remission of ovarian carcinoma IL-2 T cell proliferation and activation, NK cell activation remission in renal cell carcinoma and melanoma TNF macrophage and lymphocyte activation reduction in malignant ascites Cytokine immunotherapy

nActive Immunization: The host actively elicits an immune response. n Specific nVaccination with viral Ags: e.g. n Hepatitis B virus n Human Papilloma virus (HPV) nActive Immunization: The host actively elicits an immune response. n Specific nVaccination with viral Ags: e.g. n Hepatitis B virus n Human Papilloma virus (HPV)

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