Objectives Introduction Ags expressed by cancer cells Nature of immune response How cancer evades immune system Immunotherapy

Cancer Introduction Uncontrolled growth produces a tumor or neoplasm. A tumor that grows indefinitely and often spreads (metastasis) is called malignant--also called cancer. A tumor that is not capable of indefinite growth----benign. Malignant---kills host. Benign---does not kill host.

Molecular Basis of Cancer Radiation Chemical (Carcinogen) Virus Mutations Uncontrolled cell growth Proto-oncogenes Tumor-suppressor genes

Types of cancers based on etiologic agent Chemically-induced tumors Each tumor induced by a carcinogen (e.g. benzopyrene) injected at various sites expresses a unique Ag. Thus difficult to develop vaccine. Virus-induced tumors Tumors induced by same virus express same tumor Ag. Induce a strong immune response. Human Papilloma Virus (HPV) induced cervical cancer UV-induced tumors UV radiation--->melanomas Highly tumorigenic

Evidence for the role of immune system in tumor rejection 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)

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 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

Other Tumor associated antigens Differentiation Ags: B cells produce surface Ig. B cell tumors have sIg Overexpression of Ag on tumors compared to normal cells e.g. In breast cancer, HER2/neu Ags expressed on male germ cells and melanoma e.g. MAGE-1

Tumor Antigen

Antitumor Effector Mechanisms Immune surveillance : Recognize and destroy clones of transformed cells before they grow into tumors and to kill tumors after they are formed. NK cell Cytotoxic T-cell Humoral Mechanisms Macrophage

Tumor Immunity

Tumor and activated T cells Two major pathways for TCL: Fas-mediated and perforrin-mediated

How does a tumor escape immune surveillance? Generation of Regulatory cells (CD4+CD25+ FoxP3+ T cells) or Myeloid-derived suppressor cells(Gr-1+ CD11b+) Secrete immunosuppressive molecules Ex: Transforming growth factor beta (TGF-b), interleukin-10 (IL-10), etc. T regs CTL Tumor MDSC IL-10, etc

Failure to process and present tumor Ag. Macrophage tumor Ag tumor B cell MHC Class II T helper (Th) cell MHC Class I Cytotoxic T lymphocyte (CTL) tumor tumor

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

Downregulation of MHC expression on tumor cell (CTL resistant but NK sensitive) NK cell Tumor cell

Tumor escape mechanisms: Fas FasL Tumor CTL FasL Fas Tumor CTL When tumor cells express Fas Ligand, they can kill Fas+ T cells, thereby escaping immune destruction.

Traditional approaches to treat cancer Surgery Radiation Chemotherapy Localized tumors Metastastic tumors Affects proliferating cells (bone marrow, etc.) Radiation/Drug-resistant tumors Novel Mode: Immunotherapy

Immunotherapy Active Immunization: The host actively elicits an immune response. Specific Vaccination with viral Ags: e.g. Hepatitis B virus Human Papilloma virus (HPV) - Gardasil

Nonspecific: BCG (Bacillus Calmette-Guerin) Mycobacteria - melanoma, bladder carcinoma Normal Mf Tumor Activated lysis

Passive Immunization: Preformed Abs or immune cells transferred Specific: Ab Therapy Abs against growth factor receptor e.g. IL-2R in HTLV-1 induced Adult T cell leukemia Abs specific for oncogene product e.g. Abs against HER2/neu (Herceptin or trastuzumab) IL-2R IL-2 Anti-IL-2R

Anti-tumor Abs coupled to toxin, radioisotopes, drugs or enzymes: Immunotoxins: Ricin A/diphtheria/Pseudomonas toxin coupled to Abs. e.g. antiCD20-Pseudomonas toxin in B cell leukemia Internalized toxin inhibits protein synthesis. Tumor Ricin

Cytokine Therapy Inject cytokines. 1. Interleukin -2 (IL-2) high dose - Alone or with cells Melanoma and renal cell carcinoma Activates NK and CTL Toxic - fever, edema, shock 2. Tumor necrosis factor (TNF-a) -Carcinoma

SUMMARY Tumors should express TSTA. Th cells and CTL are important in tumor rejection. NK cells and macrophages also play an important role. Tumors evade immune system in a number of ways. Immunotherapy is promising.