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Immunity to tumors. Tumor antigens Immune system’s reaction to tumor antigens How tumors evade the immune system Immunologic approaches to treatment of cancer. Cancers arise from the uncontrolled proliferation and spread of clones of malignantly transformed cells .
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Immunity to tumors • Tumor antigens • Immune system’s reaction to tumor antigens • How tumors evadethe immune system • Immunologic approaches to treatment of cancer
Cancers arise from theuncontrolledproliferation and spreadofclonesofmalignantlytransformedcells. Cancer is a major causeofdisease and death. About 1 of 5 deaths in industrialisedcountries is from cancer.
The immune surveillancehypothesis Frank MacfarlaneBurnet 1956: The immune system constantlychecksourcells, and detects and destroysthosethataremalignantlytransformed.
Contra: Most tumors are not more common in immunodeficientindividuals. Exception: Virus-induced tumors.
Tumors are «self», not «foreign». Theydon’t have PAMPs, like pathogens do. 2) Most tumor cellslack HLA class II and costimulatorymolecules.
3) Tumors that do not cause inflammationmayinduce DC- mediatedtolerance. 4) Naive T cellscirculate in blood, lymph and secondarylymphoid organs, and do not usuallyenter peripheraltissues.
Tumor antigens: • Tumor-specific • Unique to individual tumors • Sharedamong tumors • Tumor-associated • Viral antigens
Mutated forms of cellular genes not involved in tumorigenesis: Various mutated proteins in melanomas recognized by CTLs
Products of oncogenes and tumor suppressor genes: Oncogene products: Ras mutations (∼10% of human carcinomas), p210 tyrosine kinase product of Bcr/Ablchromosomal rearrangements (CML). Tumor suppressor gene products: Mutated p53 (present in ∼50% of human tumors).
Unmutated but overexpressed products of oncogenes: HER2/Neu(tyrosine kinase; breast and other carcinomas)
Products of genes that are silent in most normal tissues: Cancer/testis antigens expressed in melanomas and many carcinomas; normally expressed mainly in the testis and placenta
Normal proteins overexpressed in tumor cells: Tyrosinase, gp100, MART in melanomas (normally expressed in melanocytes)
Oncofetalantigens: Silenced during development, de-repressedwithmalignanttransformation. Diagnostictools. Carcinoembryonicantigen (CD66) on many tumors, also expressed in liver and other tissues during inflammation. α-Fetoprotein(alsoelevated in some non-neoplasticdiseases).
Glycolipids and glycoproteins: • Gangliosides • Mucins
Tissue-specific differentiation antigens: Prostate-specific antigen in prostate carcinomasCD20 on B cell lymphomas
Products ofoncogenicviruses: Papillomavirus E6 and E7 proteins (cervical carcinomas) HPV vaccination EBNA-1 protein ofEpstein-Barr Virus (EBV-associatedlymphomas, nasopharyngealcarcinoma)
Immune responses to tumors • Innate immunity • NK cells, macrophages • Adaptive immunity • T lymphocytes, antibodies
NK cells Kill manycells in vitro, especiallycellswithlowexpressionof MHC class I. ADCC In vivo importanceunclear. LAK cells
Macrophages M1 Mφ: Can kill tumor cells M2 Mφ: Canpromote tumor growth
The principalmechanismof adaptive tumor immunity is killing of tumor cells by CD8+CTLs.
Inductionof CTL responses to tumors by dendriticcell cross-presentation.
Antibodies Little evidence for in vivo killing of tumors by host antibodies.
Evasionof immune responses by tumors. Tumor editing – tumors become less immunogenic over time.
Intrinsicmechanismsofevasion • Loss of antigen expression • Lackofcostimulators or HLA class II • Inhibitoryfactors
Extrinsicfactors • Macrophageswith M2 phenotype • Regulatory T cells • Myeloid-derivedsuppressorcells
Immunotherapy for tumors: • More specific and fewer side effectsthancurrenttherapies. • Stimulationofactive host immune responses or • Passive immunotherapy
Stimulationofactive host immune responses • Vaccinationwith tumor antigens • Useofcostimulators and cytokines • Blockinginhibitorypathways • Nonspecificstimulation
Tumor vaccines Type of Vaccine Vaccine Preparation Killed tumor vaccine Killed tumor cells + adjuvants Tumor cell lysates + adjuvants Purified tumor antigens Dendritic cell-based Dendritic cells pulsed with vaccines tumor antigens Dendritic cells transfected with genes encoding tumor antigens
Enhancement of tumor cellimmunogenicity by transfectionofcostimulator and cytokine genes
N Eng J Med July 11 2013 Nivolumab: Anti PD1 receptor Ipilimumab: Anti CTLA-4 (PD1 and CTLA-4 dampen T cellactivity.)
Non-specificstimulation by systemiccytokinetherapy (a limitedsuccess). IL-2 (Melanoma, renal & colon cancer) IFN-α (Melanoma, carcinoid tumor) TNF (Sarcoma, melanoma) GM-CSF (to promote bone marrow recovery)
Passive immunotherapy • Adoptive cellular therapy • Anti-tumor antibodies
Adoptive cellular therapy LAK cells
Anti-tumor antibodies. Mouse Ig is immunogenic for humans. «Humanization» ofmouseIg.
Mabs used in cancer treatment in Norway: Alemtuzumab CD52 Chroniclymphaticleukemia Bevacizumab VEGF Several cancer forms Cetuximab, Panitumumab EGFR EGFR+ colorectal cancer
Rituximab, CD20 Non-Hodgkinlymphoma, chroniclymphaticleukemia Ofatumumab CD20 Chroniclymphaticleukemia Trastuzumab Her2 Her2+ mamma cancer
Pertuzumab Her2R Her2+ mamma cancer Ipilimumab CTLA-4 Malignantmelanoma
Catumaksomab EpCAM + CD3 Malign ascites(ascites is abnormalaccumulationof fluid in theabdominal cavity).
Promotionof tumor growthby the immune system: • Chronicinflammation • Hepatitis B • Mutationscaused by freeradicals • Growth factors • M2 macrophages (VEGF, TGF-β)