Transcript Tumor Immunology
Tumor Immunology
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
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”
Four Primary Functions
• • • • Recognition of self – self-tolerance – immunological privilege Immunosurveillance Intracellular hormones Defense against infection
Role of the immune system
Virus Influenza
Polio mellitus
is to protect from:
Parasites Tapeworms Malaria Helminths Fungi
Candida albicans
Bacteria
Tubercule bacillus Staphylococci
Origin of cells involved in the immune response Haemopoietic stem cell Myeloid progenitor Monocyte Lymphocyte progenitor Dendritic cell NK cell Thymus B cell CD8 T cell CD4 T cell Plasma cell Basophil Mast cell Eosinophil Macrophage Neutrophil
3 Types of Actions of the Immune System
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
Spontaneous regression
Infiltration of tumors by lymphocytes and macrophages
Regression of metastases after removal of primary tumor
Regression after chemotherapy
Lymphocyte proliferation in draining lymph nodes
Higher incidence of cancer after immunosuppression/immunodeficiency (AIDS, neonates, aged, transplant patients)
Association between immunodeficiency and cancer cause of immuno deficiency primary (inherited) immunodeficiency secondary (acquired) immunodeficiency malaria autoimmunity malignancy lymphomas lymphoma, cervical cancer, liver cancer, skin cancer, Kaposi’s sarcoma.
Burkitt’s lymphoma lymphoma
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
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
Tumor-specific transplantation Ag
TATA
Tumor-associated transplantation Ag
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 associated transplantation antigens
:
shared Ag on virally induced tumors
Discovery of tumor specific transplantation antigens, TSTA
Tumor-Associated Developmental Ags
Found on cancer cells and on fetal cells.
Do not trigger anti-tumor immunity.
Used in diagnosis.
Alpha-fetoprotein(AFP) Cancers of liver
Carcinoembryonic Ag (CEA) colorectal cancer
Breast cancer
CA 15-3
Ovarial 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 may fail to express costimulatory molecules involved in T cell activation.
tumor Class I MHC tumor Ag B7 CD28 CTL Tumors escape the action of CTL by not expressing B7 which provides 2 nd signal 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
Use of tumor associated antigens monoclonal antibodies
Monoclonal antibodies: use as a diagnostic tool
Immunotherapy of tumors
specific non specific active immunotherapy killed tumor cells, purified or recombinant Ag BCG, Propionibacterium acne, levamisole, etc.
non-specific specific passive immunotherapy LAK cells, cytokines antibodies alone or conjugated with other agent, activated T cells
Non-specific immunotherapy
BCG, P. acnes, muramyl dipeptide bacterial products activate macrophages and NK cells (via cytokines) pyran, poly I:C synthetic molecules interferon production cytokines IFN , IFN , IFN , IL-2, TNF activate macrophages and NK cells
IFN IFN IL-2 TNF
Cytokine immunotherapy
remission of hairy cell leukemia, weak effect on carcinomas remission of ovarian carcinoma remission in renal cell carcinoma and melanoma reduction in malignant ascites increased expression of class-I MHC, possible anti tumor effect increased expression of class-I MHC, Tc and NK cell activation T cell proliferation and activation, NK cell activation macrophage and lymphocyte activation
Active Immunization: The host actively elicits an immune response.
Specific
Vaccination with viral Ags: e.g.
Hepatitis B virus
Human Papilloma virus (HPV)