Tumor Immunology

Learning Objectives n n Etiology of cancer n n Mechanisms by which immune system recognize tumors n n Understand tumor escape mechanisms n n Learn how to manipulate the immune system to kill tumors: immunotherapy

Tumor n n Cells that continue to replicate, fail to differentiate into specialized cells, and become immortal Malignant: A tumor that grows indefinitely and spreads (metastasis)--also called cancer: kills host Benign: A tumor that is not capable of metastasis: does not kill host muscle, nerve, bone, blood

Types of Cancer n n Carcinoma: arising from epithelial tissue, such as glands, breast, skin, and linings of the urogenital, digestive, and respiratory systems (89.3% of all cancers) n n Sarcoma: solid tumors of muscles, bone, and cartilage that arise from the embryological mesoderm (1.9% of all cancers) n n Leukemia: disease of bone marrow causing excessive production of leukocytes (3.4% of all cancers) n n Lymphoma, Myeloma: diseases of the lymph nodes and spleen that cause excessive production of lymphocytes (5.4% of cancers)

Etiology of Cancer Genetic factors: mutations, translocation, amplifications Environmental factors: UV, chemicals, viral infections n n conversion of proto-oncogenes (potential for cell transformation) to oncogenes (cell transformation) n n alteration in tumor suppressor genes

Cell Growth Control of cell growth Growth-promoting Proto-oncogenes Growth-restricting Tumor-suppressor genes

Molecular Basis of Cancer Uncontrolled cell growth Conversion of proto- oncogenes to oncogenes: amplification of c-erbB2 in breast cancer point mutation of c-ras in kidney and bladder cancers chromosome translocation of c-myc in Burkitt’s lymphoma Altered tumor-suppressor genes: P53 mutation in prostate cancer: failure in cell cycle arrest or apoptosis of prostate tumors Rb mutation: fail to prevent mitosis

Epigenetic Factors

Genetic Factors

UV-induced Cancers n n Damage or mutation of DNA: n n Melanoma: metastatic, highly immunogenic, spontaneous rejection n n Non-melanoma cancers: Basal cell carcinoma: rarely spreads Squamous cell carcinoma: can spread

Chemically-induced Cancers n n Free radicals and other oxidants steal electron from DNA and cause cancer: anti- oxidants (vitamins A, C)

Virally-induced Cancers DNA viruses: papova (papilloma, SV40), hepatitis, EBV RNA viruses: retroviruses---> Human T- lymphotropic viruses (HTLV-I and HTLV-II) cause T cell leukemia Highly immunogenic because of viral antigens

Evidence for Tumor Immunity n n Spontaneous regression: melanoma, lymphoma n n Regression of metastases after removal of primary tumor: pulmonary metastases from renal carcinoma n n Infiltration of tumors by lymphocytes and macrophages: melanoma and breast cancer n n Lymphocyte proliferation in draining lymph nodes n n Higher incidence of cancer after immunosuppression, immunodeficiency (AIDS, neonates), aging, etc.

Tumor-specific Immune Response

Tumor Immunology n n Cancer immunosurveilance: immune system can recognize and destroy nascent transformed cells n n Cancer immunoediting: immune system kill and also induce changes in the tumor resulting in tumor escape and recurrence (epigenetic changes or Darwinian selection)

Immune Recognition of Tumor Antibodies recognize intact antigens while T cells recognize processed antigens associated with MHC

Immune Recognition of Tumor n n Repertoire of T cells with low affinity against self proteins exist because of positive and negative selections in the thymus n n Expression of altered self proteins by tumors will increase the affinity of T cells for tumor antigens

Altered Self Proteins and Co- stimulatory Molecules n n Mutated self antigens n n Antigen mimicry: viral antigens n n Expression of cryptic or hidden epitopes n n Expression of co-stimulatory molecules in tumors or cross presentation of tumor antigens by antigen presenting cells (APC)

Tumor antigens Cervical cancerviral transforming gene product HPV (E7) TSA (Tumor Specific Antigen) Melanomamelanin polymerization gp100 Breast, ovary, GI, lung, prostate Breast Colorectal cancer receptor tyrosine kinase lubs of epithelia cell adhesion HER-2/neu ERBB3 ERBB4 MUC-1 CEA TAA (Tumor Associated Antigen) Melanomamelanin synthesisTyrosinase TDA (Tumor Differentiation Antigen) Melanoma Breast & Glioma normal testicular protein MAGE1 MAGE3 CTA (Cancer Testis Antigen) cancersfunctionantigen

Activation of naïve T cells Signal I Signal II Effector T cells: killers T cells Tumor Cross Presentation of Tumor Antigens

Tumor killing Non-specific: NK cells,  T cells (NKG2D), macrophages, NK T cells Antigen-specific: Antibody (ADCC, opsinization); T cells (cytokines, Fas- L, perforin/granzyme)

Non-specific Tumor Killing NKT Tumor MIC A, B NK T cells IFN-  Perforin/granzyme B Fas-L/Fas apoptosis NKG2D

Antigen-specific tumor killing: B cells (opsinization & ADCC) sIg Tumor Complement Macrophage/ opsinization FcR FabFc NK cells & ADCC Tumor

Antigen-specific Tumor Killing: B Cells (blocking) IL-2R IL-2 Anti-IL-2R Ab T cell leukemia

Antigen-specific Tumor Killing: T Cells MHCI peptide Apoptosis T cell receptor (TCR) CD8 Tumor IFN-  Granzyme B

Cancer Immunotherapy How to kill tumors without killing normal cells? To induce an immune response against the tumor that would discriminate between the tumor and normal cells: Adaptive immunity

Tumor antigens Tumor Specific Antigens (TSA)  Are only found on tumors  As a result of point mutations or gene rearrangement  derive from viral antigens Tumor Associated Antigens (TAA)  Found on both normal and tumor cells, but are overexpressed on cancer cells  Developmental antigens which become derepressed. (CEA)  Differentiation antigens are tissue specific  Altered modification of a protein could be an antigen

Tumor antigens

Immunotherapy Adoptive T cell therapy (AIT) Passive immunotherapy using antibodies Active-specific immunotherapy by using vaccines

AIT + IL-2 against melanoma

BeforeAfter

Transfer tumor-specific T cell receptor genes using retroviral vectors into patients’ T cell before AIT

AIT for B cell lymphoma

Passive immunotherapy

Passive immunotherapy: mAbs Herceptin: anti-HER-2/neu in breast cancer patients Rituximab: anti-CD20 in patients with non- Hodgkin’s lymphoma Bevacizumab: anti-VEGF in patients with advanced colorectal cancer Limitations: clearance by soluble Ags, antigenic variation of the tumor, inefficient killing or penetration into the tumor mass

Passive immunotherapy: immunotoxins Anti-CD22 Ab fused to a fragment of Pseudomonas toxin in patients with B-cell leukemia (hairy-cell leukemia)

Passive immunotherapy: drug-linked antibodies Anti-CD20 antibodies linked to a radioisotope yttrium-90 in patients with refractory B-cell lymphoma Antibody-directed enzyme/pro-drug therapy (ADEPT): Antibodies linked to an enzyme that metabolizes a nontoxic pro-drug to the active cytotoxic drug

Signal I Signal II T cells Tumor Vaccination: cross presentation of tumor antigens by APCs T cell activationT cell killer function

Vaccination Cell-based vaccines using irradiated tumors with adjuvants such as BCG Peptide- and protein-based vaccines DNA vaccines

Vaccination: increase immunogenicity of tumor cells

Vaccination HPV vaccine for the prevention of cervical cancer Oncophage (gp96): a tumor-derived heat shock protein vaccine against kidney cancer and melanoma

Vaccination: Oncophage

Both genetic and environmental factors are involved in tumor formation Immune system plays a surveillance role in controlling the development of cancer, however, it also induces epigenetic changes in tumors that result in cancer (immune editing) Altered expression of antigens by tumors (mutation, viral antigens, cryptic epitopes), expression of co- stimulatory molecules in tumors, or cross-presentation of tumor antigens by APC results in the immune recognition of tumor cells Summary

Manipulation of tumors for the expression of new antigens is a promising approach for the induction of anti-tumor immune responses Vaccines may be effective against residual tumors but AIT and passive immunotherapy have potentials for the treatment of primary tumors Summary