Tumor Immunology

Key questions:  How do tumor cells evade the immune system  What are the main immune responses to tumor cells?  What are the potential anti-tumor immunotherapies?

23.Tumor Immunology a.Properties of tumor (transformed) cells (1)Abnormalities in growth and responses to regulation and apoptosis (2)Induction by carcinogens, viruses; spontaneous (3)Role of oncogenes (e.g. growth-promoting oncogenes and oncoproteins) (4)Role of tumor-suppressor genes and genes that control DNA repair CORE

Cancer Cancer is caused by abnormal and invasive growth of tumor cells It accounts for 20% of death in industrialized countries. 6 million new cancer patients each year worldwide. Generally, cancer occurs late in life. Caused by accumulated mutations in the genes controlling cell growth and death. Current treatments: surgery, radiation and cytotoxic drugs Future treatments: small molecule drugs that specifically inhibit tumor cell growth; immunotherapy

Carcinogens induce mutations in DNA: Chemical carcinogens Radiation Oncogenic viruses (& chronic infection/inflammation)

Accumulation of mutations leads to cancer cells

The growth and lifespan of a typical human tumor

Benign vs. malignant tumors Breast tumors for example Malignant cells are more aggressive in growth, and they spread to nearby tissues or to different organs through lymph and blood vessels (Metastasis)

Carcinoma: epithelial cell tumors Leukemia: tumors of circulating cells Lymphoma: solid tumors in lymph nodes Myeloma: tumors of bone marrow cells Sarcoma: tumors of connective tissue cells Terminologies

Viruses are associated with some human cancers Some viral proteins induce unchecked proliferation of human cells by targeting genes such as P53 and Rb

Can tumor cells from a person grow in another person? Usually, no. But sometimes, yes. Largely, it depends on the MHC haplotype of donors and recipients.

How do immune cells detect tumor cells? CD4, CD8, NK cells and B cells They look for tumor antigens, antigens differentially expressed by tumor cells and normal cells. Tumor antigens: Changes in the genome of tumor cells can lead to the expression of tumor antigens, which are not (tumor- specific antigens) or less expressed in normal cells (tumor-associated antigens).

b.Tumor-specific and tumor-associated antigens (1)Tumor-specific shared antigens: melanoma antigen-1 (MAGE-1); found on melanomas and other transformed cells (2)Tissue-specific antigens (on normal and transformed cells; such as tyrosinase found on normal and transformed melanocytes) (3)Antigens resulting from mutation (such as mutations of oncogenes) (4)Over expressed antigens; antigens expressed at abnormal stage of development (5)Viral antigens (6)Other cancer indicators: (a) Oncofetal antigens: Carcinoembryonic antigen (CEA): Colon cancer Alpha-fetoprotein: Liver and testis cancer (b) Differentiation antigens: Common acute lymphoblastic leukemia antigen (CALLA, also called CD10) found on cells of acute lymphoblastic leukemia PSA (Prostate cancer) CORE

Tumor antigens Qualitative and/or quantitative changes in antigen

Tumor Epitope Escape Mutation of anchor residues Mutation of TCR contact residues No CTL recognition Antagonistic Epitope => negative signal to CTL (Altered Peptide Ligand [APL]) Mutation affecting antigen processing Within epitope affecting stability of epitope Outside of epitope efficiency of epitope processing Tumor antigens

Examples of tumor antigens recognized by CD8 T cells

c.Anti-tumor immunity (1)CMI (TC, TH1 cytokines, NK, macrophage) (2)Humoral (ADCC and activation of complement) (3)"Immunosurveillance": There is an increased frequency of cancers in immunocompromised individuals, however, most cancers occur in individuals with no overt immunodeficiency. More likely that tumors develop ways of evading the immune system. CORE

Anti-tumor immunity Cell-mediated immune response: CD4 T cells: control other immune cells by cytokines CD8 T cells: direct lysis NK cells: direct lysis Eosinophils: degranulation Humoral response by B cells: Antibodies to tumor cells 1. facilitate NK cell-mediated lysis of tumor cells 2. activate complement reaction

NK cells can attack tumor cells lacking MHC I expression NK cells tumor cells

Tumor antigen specific CD4 + and CD8 + T cells

Figure DCs present tumor antigens to CD4 and CD8 T cells. Membrane fusion allows presentation of tumor Ag to CD8 T cells.

How do tumors evade immune responses? (4)Examples of tumor evasion: (a)out-growth of antigen-negative variants (b)loss or reduced expression of MHC proteins (c)secretion of immunosuppressive cytokines (d)inducing CTL apoptosis (e)lack of co-stimulatory signals (f)soluble tumor antigens CORE

Mechanisms of tumor cell evasion of anti-tumor cells Defective in one or more of their MHC class I expression (30-50% of tumors are defective in MHC I expression) Production of suppressive cytokines (TGF-beta and Th2 cytokines), which suppress cell-mediated immune response Lack of co-stimulatory signals Out-growth of antigen-negative variants Shedding of MHC class I-related chain (MIC), a ligand of NKG2D that is an activating NK cell receptor, by epithelial tumor cells to inhibit NKG2D + NK cells

Figure Loss of MHC class I expression in prostate tumor cells

d.Immunotherapy (1)Non-specific stimulation (adjuvant therapy) (2)Active immunization with tumor antigens; role of co-stimulatory molecules (3)Cytokine therapy (4)Adoptive cellular immunotherapy (LAK cells, TIL) (5)Anti-tumor antibodies (coupled to cytotoxins or radioisotopes) CORE

Non-specific adjuvant therapy Introduction of BCG vaccine (killed mycobacterium) into the bladder is a treatment for superficial bladder cancer This may be because: Bacterial products or adjuvants increase the T cell response by activating antigen presenting cells and other cells through TLRs. This will also induce co- stimulation molecules and MHC molecules on APCs.

Potential immunotherapies against tumor cells Antibody against tumor antigen (immunotoxins and induction of ADCC by NK cells). Tumor vaccines: tumors taken at surgery are manipulated ex vivo (out of body) and are used as vaccine. This manipulation includes expressing B7, GM-CSF or IL-12 in tumor cells. Tumor antigens can be used as vaccines too. e.g. CEA (carcinoembryonic antigen), HSP (heat shock protein), and telomerase. Dendritic cell therapy: dendritic cells are isolated from patients and are loaded with tumor antigen peptides in vitro. These cells are injected into patients to boost anti-tumor T cell response. T cell therapy: patients’ T cells, activated in vitro with tumor antigens and cytokines (IL-12), are injected back to the patients.

Monoclonal antibodies for cancer therapy Rituxan. Anti-CD20, a cell surface marker found on most B cells. Certain non- Hodgkins lymphomas. Herceptin. Anti-EFG-receptor-2 (also known as HER2, ErbB2 or Neu), which is overexpressed in ~25 percent of breast cancers. Erbitux, anti-EGFR (HER1), approved for metastatic colorectal cancer Avastin. Blocks the vascular endothelial growth factor (VEGF) receptor. An anti-angiogenesis drug. Radiolabeled MAbs Zevalin- A radiolabeled MAb to treat B cell non-Hodgkin lymphoma that has not responded to standard treatment. Bexxar - A radiolabeled MAb to treat certain types of non-Hodgkin lymphoma that no longer respond to rituximab (Rituxan) or chemotherapy. Radiolabeled antibodies approved by the FDA to detect cancer. OncoScint (for colorectal and ovarian cancer) ProstaScint (for prostate cancer).

Figure Immunization with MAGE-1/3 induces anti-melanoma immune response

Monoclonal antibodies to tumor antigens can deliver toxins or NK cells to tumor cells