Medical Immunology Department of Immunology Yiwei Chu Chapter

Medical Immunology Department of Immunology Yiwei Chu

Chapter 17 Immunity to tumors June, 21, 2010 DEPARTMENT OF IMMUNOLOGY

Content 1. General Features 2. Tumor antigen 3. Immune Responses 4. Evasion of Immune Responses 5. Immunotherapy DEPARTMENT OF IMMUNOLOGY

Cancer is a major health problem worldwide and one of the most important causes of morbidity and mortality in children and adults. DEPARTMENT OF IMMUNOLOGY

Robin Bush The sister of George W. Bush, die from leukemia, at the age of 4. Walt Disney This famous animator, producer and co-founder of the corporation known as The Walt Disney Company died at the age of 65 from lung cancer, making him one of the most famous celebrities to have died from smoking. Paul Newman was of course a great actor, but was known well for his healthy line of food. He struggled with lung cancer, and passed away on September 26, 2008, at the age of 83. DEPARTMENT OF IMMUNOLOGY

General Features v Tumor express antigens that are recognized as foreign by the immune system of the tumor-bearing host. v Immune responses frequently fail to prevent the growth of tumors. v The immune system can be activated external stimuli to effectively kill tumor cells and eradicate tumors. DEPARTMENT OF IMMUNOLOGY

Tumor Antigen DEPARTMENT OF IMMUNOLOGY

v Immune responses frequently fail to prevent the growth of tumors v First, tumor cells are derived from host cells. v Second, the rapid growth and spread of tumors v Third, specialized mechanisms for evading host immune responses. DEPARTMENT OF IMMUNOLOGY

Content 1. General Features 2. Tumor antigen 3. Immune Responses 4. Evasion of Immune Responses 5. Immunotherapy DEPARTMENT OF IMMUNOLOGY

Tumor Antigen The earliest classification: v Tumor-specific antigen v Tumor-associated antigen DEPARTMENT OF IMMUNOLOGY

Tumor Antigen v Tumor-specific antigen Antigen that are expressed on tumor cells but not on normal cells were called tumor- specific antigens; some of these antigens are unique to individual tumors, whereas others are shared among tumors of the same type. DEPARTMENT OF IMMUNOLOGY

Tumor Antigen v Tumor-associated antigen Tumor antigens that are also expressed on normal cells were called tumor-associated antigens; in most cases, these antigens are normal cellular constituents whose expression is aberrant or dysregulated in tumors DEPARTMENT OF IMMUNOLOGY

Tumor Antigen DEPARTMENT OF IMMUNOLOGY

Tumor Antigen The modern classification is relies on the molecular structure and source of the antigen DEPARTMENT OF IMMUNOLOGY

Tumor Antigen DEPARTMENT OF IMMUNOLOGY

Tumor Antigen Type of antigen Examples of human tumor antigens Products of oncogenes, tumor suppressor genes Oncogenes: Ras mutations (∼ 10% of human carcinomas), p 210 product of Bcr/Abl rearrangements (CML), overexpressed Her 2/neu (breast and other carcinomas) Tumor supressor genes: mutated p 53 (present in ∼ 50% of human tumors) Mutants of cellular genes not involved in tumorigenesis p 91 A mutation in mutagenized murine mastocytoma; various mutated proteins in melanomas recognized by CTLs 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 Products of overexpressed genes Tyrosinase, gp 100, MART in melanomas (normally expressed in melanocytes) Products of oncogenic viruses Papillomavirus E 6 and E 7 proteins (cervical carcinomas) EBNA-1 protein of EBV (EBV-associated lymphomas, nasopharyngeal carcinoma) SV 40 T antigen (SV 40 -induced rodent tumors) Oncofetal antigens Carcinoembryonic antigen (CEA) on many tumors, also expressed in liver and other tissues during inflammation Alpha-fetoprotein (AFP) Glycolipids and glycoproteins GM 2 GD 2 on melanomas Differentiation antigens normally present in tissue of origin Prostate-specific antigen Markers of lymphocytes: CD 10, CD 20, Ig idiotypes on B cells DEPARTMENT OF IMMUNOLOGY

Content 1. General Features 2. Tumor antigen 3. Immune Responses 4. Evasion of Immune Responses 5. Immunotherapy DEPARTMENT OF IMMUNOLOGY

Immune Responses to Tumors v T lymphocytes v Antibodies v NK cells v Macrophages DEPARTMENT OF IMMUNOLOGY

Immune Responses to Tumors v T lymphocytes The killing of tumor cells by CD 8+ CTL DEPARTMENT OF IMMUNOLOGY

Immune Responses to Tumors v T lymphocytes DEPARTMENT OF IMMUNOLOGY

DEPARTMENT OF IMMUNOLOGY

Immune Responses to Tumors v T lymphocytes DEPARTMENT OF IMMUNOLOGY

Immune Responses to Tumors v Antibodies The killing of tumor cells by activating complement or by ADCC DEPARTMENT OF IMMUNOLOGY

Immune Responses to Tumors Complement System DEPARTMENT OF IMMUNOLOGY

Immune Responses to Tumors DEPARTMENT OF IMMUNOLOGY

Immune Responses to Tumors v NK cells kill many types of tumor cells, especially cells that have reduces class I MHC expression and can escape killing CTLs. DEPARTMENT OF IMMUNOLOGY

engagement of inhibitory NK cell receptors such as KIR and CD 94/NKG 2 by class I MHC molecules delivers an inhibitory signal that counteracts the activation signal. DEPARTMENT OF IMMUNOLOGY

Immune Responses to Tumors v NK cells DEPARTMENT OF IMMUNOLOGY

Immune Responses to Tumors v Macrophages Dual role of macrophages in tumor growth and angiogenesis: v They activate and present tumor antigens to T cells, which are then activated to kill tumor cells. v However, tumor cells are often capable of escaping the immune machinery. As the immune surveillance is not sufficient anymore, tumor-associated macrophages contribute to tumor progression. DEPARTMENT OF IMMUNOLOGY

Content 1. General Features 2. Tumor antigen 3. Immune Responses 4. Evasion of Immune Responses 5. Immunotherapy DEPARTMENT OF IMMUNOLOGY

Evasion of Immune Responses The key of tumor growth, migration and metastasis is that tumor cells evade immune destruction, often called tumor escape. Turk MJ, J. Exp. Med. 2004, 200(6): 771 -782 Hori S: Science, 2003, 299: 1057 -1061 Jun Shimizu et al: Nat. Immunology. 2002, 3(2): 135 -142 Shevach. EM: Nat Rev. Immunol. 2002, 2: 389 -400 DEPARTMENT OF IMMUNOLOGY

Evasion of Immune Responses v Class I MHC expression may be down-regulated on tumor cells so that they cannot be recognized by CTLs. v Tumor lose expression of antigen that elicit immune responses. v Tumors may fail to induce CTLs because most tumor cells do not express costimulators or class II MHC molecules. v The products of tumor cells may suppress antitumor immune responses. v Tumor antigens may induce specific immunologic tolerance. DEPARTMENT OF IMMUNOLOGY

Evasion of Immune Responses CD 4+CD 25+Treg：Negative regulator ØExisting a large amount of CD 4+CD 25+Tregs in TILs ØRegrssion the tumorigenesis if deleting the CD 4+CD 25+Treg Tyler J. Curiel et al: Nature Medicine. 2004, 10(9): 942 -949 Zhang, L et al: N. Engl. J. Med. 2003, 348: 201 -213 DEPARTMENT OF IMMUNOLOGY

Content 1. General Features 2. Tumor antigen 3. Immune Responses 4. Evasion of Immune Responses 5. Immunotherapy DEPARTMENT OF IMMUNOLOGY

Immunotherapy v History Cancer Immunosurveillance Hypothesis (Controversy to Resolution) ‘Inheritable genetic changes must be common in somatic cells and a proportion of these change will represent a step toward malignancy. It is an evolutionary necessity that there should be some mechanism for eliminating or inactivating such potentially dangerous mutant cells and it is postulated that this mechanism is of immunological character’ ----- Sir Mac. Farlane Burnet, 1964 Fundamental Prediction: Immunodeficient individuals should show a significant increase in tumor incidence. However, ‘Athymic-nude mice and normal mice showed no differences in either latent period or incidence of local sarcomas or lung adenomas within 120 days after administration of 3 -methylcholanthrene at birth’ ----- Stutman O, et al. Science 183(4124): 534. 1974 DEPARTMENT OF IMMUNOLOGY

Immunotherapy v 27 years later…. Resolution Ø Increased Incidence of MAC-Induced Tumor Detected In Mice With Well-Defined Genetic Immunodeficiencies. Shankaran et al. Nature 410: 1107 -1111 2001 Ø An accumulation of immune cells at tumor sites correlates with improved prognosis. Zhang et al. N Engl J Med 348: 203 -213 2003 Ø First human melanoma tumor antigen (MAGE-1) was identified. T Boon et al. Science, Vol 254, Issue 5038, 1643 -1647 1991 DEPARTMENT OF IMMUNOLOGY

Immunotherapy • Active immunotherapy • Passive immunotherapy DEPARTMENT OF IMMUNOLOGY

Immunotherapy Active immunotherapy • Vaccination • Augmentation of host immunity to tumors with cytokines and costimulators DEPARTMENT OF IMMUNOLOGY

Immunotherapy Active immunotherapy------Vaccination 1. Killed tumor vaccine 2. Purified tumor antigens 3. Professional APC-based vaccines 4. Cytokine- and costimulator-enhanced vaccines 5. DNA vaccines 6. Viral vectors DEPARTMENT OF IMMUNOLOGY

Immunotherapy DEPARTMENT OF IMMUNOLOGY

Immunotherapy Dendritic Cell- Based Vaccines Myeloma cell Tumor Biopsy + Vaccine Production Fusion + Leukapheresis Dendritic Cells Immunization with Antigen-pulsed DCs Tumor Idiotype Protein As tumor specificantigen Co-culture Regression of Lymphoma following vaccination with Id-pulsed DC Levy R, Englman E, et al. Blood 2002, 90: 1517 -1526 DEPARTMENT OF IMMUNOLOGY

Immunotherapy Augmentation of host immunity to tumors DEPARTMENT OF IMMUNOLOGY

Immunotherapy Passive immunotherapy 1. Adoptive Cellular Therapy 2. Anti-tumor Antibodies DEPARTMENT OF IMMUNOLOGY

Immunotherapy Adoptive cellular therapy DEPARTMENT OF IMMUNOLOGY

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Immunotherapy Anti-tumor Antibodies Her-2/Neu, CD 20, CD 10, CEA, CA-125, GD 3 ganglioside DEPARTMENT OF IMMUNOLOGY

Key notes Ø Concepts: TSA, TAA Ø Evasion of immune responses by tumors Ø Immunotherapy to tumors DEPARTMENT OF IMMUNOLOGY

DEPARTMENT OF IMMUNOLOGY Thank you! DEPARTMENT OF IMMUNOLOGY