Cancer and the Immune System Amar Bhatt Shirley Masand Jaime Warmkessel Immunology Chapter 22 April 22, 2003

A Look Ahead Tumors and Metastasis Oncogenes and Cancer Induction Tumor Antigens Tumors and the Immune Response Immunotherapy

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Cancer and the Immune System

Cancer “altered self-cells that have escaped normal growth regulation mechanisms” neoplasm: tumor benign vs. malignant metastasis: spreading of cancerous cells via blood or lymph to various tissues

Metastasis 22.1

Types of Cancers carcinoma: endodermal/ectodermal tissue leukemia/lymphoma: hematopoeitic stem cells sarcoma: mesodermal connective tissues

What makes cancer “cancer”? 1.decreased requirements for growth factors and serum 2.are no longer anchorage dependent 3.grow independently of density normal cells: eventually enter G o confluent monolayer CHECKPOINT FAILURE contact inhibition

Malignant Transformation  are like in vitro cancers  two phases 1.initiation (changes in genome) 2.promotion (proliferation)

Malignant Transformation  chemical and physical carcinogens  virally induced transformation  cultured tumors: good models for study  cancer cells are basically immortal

Oncogenes… oncogene: “cancer gene”; often found in viral genomes proto-oncogene: cellular counterpart which can be turned into an oncogene

What can go right?  induction of cellular proliferation  inhibition of cellular proliferation, a.k.a. tumor- suppressor genes  regulation of programmed cell death

What can go wrong?  chromosomal translocations  tandem repeats: HSRs  mutations in proto-oncogenes  viral integration  growth factors and their receptors

Induction of Cancer Fig. 22.2

Induction of Cancer

Lets Visualize!  ents/nih1/cancer/activities/activity2_anim ations.htm ents/nih1/cancer/activities/activity2_anim ations.htm ents/nih1/cancer/activities/activity2_anim ations.htm

Tumors of the Immune System  Lymphomas  Solid tumors w/in lymphoid tissue (bone marrow, lymph nodes, thymus)  Hodgkin’s & non-Hodgkin’s   Leukemias  Proliferate as single cells  Acute or Chronic depending on the progression of disease  Acute- appear suddenly and progress rapidly; arise is less mature cells (ie ALL, AML)  Chronic- much less aggressive and develop slowly; mature cells (ie CLL and CML)

Tumor Antigens  TSTAs  Tumor Specific Transplantation Antigen  TATAs  Tumor Associated Transplantation Antigen

TSTAs  Unique to tumor cells  DO NOT occur on normal cells in the body  Novel proteins created my mutation presented on class I MHC  Can either be chemically/physically induced or virally induced tumor antigens

Chemically/Physically Induced Fig 22.7 Specific Immunologic Response that can Protect against later challenge by live cells Of the same line but not other tumor-line Cells. Methylcholanthrene / UV light

Virally Induced  Express tumor antigens shared by all tumors induced by the same virus  Burkitt’s Lymphoma  Epstein Barr  HPV Fig 22.9

TATAs  NOT unique to tumor cells  DO occur on normal cells in the body  So where’s the problem?  Fetal/adult presence  Concentration of Growth Factors and Growth Factor Receptors

TATAs cont’d  Oncofetal Tumor Antigens (AFP & CEA)  Normally appear in fetus before immunocompetence  Later recognized as non-self  Oncogene Proteins  Human Melanomas

Virally Induced Tumors  Virally induced tumors have the same antigens for each tumor caused by that virus.  HPV

Immune Response to Tumors  Mostly a cell-mediated response  NK Cells  Not MHC restricted  Fc receptor binds to antibody coated tumor cell  ADCC  Chedieak-Higashi syndrome  Macrophages  Not MHC restricted  Elicits ADCC  TNF-alpha  Immune Surveillance Theory

So, you have a tumor cell. Now what?  You need three things: 1.“See” the cancer  Ternary complex and costimulation by B7 2.Activate lymphocytes  Release IL-2, IFN-gamma, and TNF-alpha 3.Cancer cells must be susceptible to killing  CTL lysis, macrophages, NK cells Info From:

But if the body has all these defenses, why do so many people still have cancer?

Conniving Cancer.  Bad antibodies?  Some antibodies do not protect against tumor growth, but also ENHANCE it.  Release of immunosuppressive cytokines  transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10) and vascular endothelial growth factor (VEGF)  Hide and go Seeking Antigen  Antigens actually seem to “hide” in the presence of antibody  Also, some cancer cells completely shed themselves of the antigen

Effect TGF-betaIL-10VEGF Inhibition of T-cell growth +-+ Inhibition of CTL differentiation +++ Inhibition of cytokine production ++- Induction of T-cell anergy +-- Downregulation of cytotoxic potential ++- Inhibition of antigen presentation ++- Shift in the Th1-Th2 balance towards Th2 ++- Downregulation of adhesion/costimulatory molecules ++- Resistance to CTL-mediated lysis -+- Source: Chouaib et al 1997

Conniving Cancer cont.  Reduction in Class I MHC Molecules

And the final blow…  Lack of Co- Stimulatory Signal

Cancer Immunotherapy  Manipulation of Co-Stimulatory Signal  Enhancement of APC Activity  Cytokine Therapy  Monoclonal Antibodies  Cancer Vaccines

Manipulation of Co- Stimulatory Signal  Tumor immunity can be enhanced by providing the co-stimulatory signal necessary for activation of CTL precursors (CTL-Ps)  Fig a

Manipulation of Co- Stimulatory Signal Cont.  Basis for Vaccine  Prevent metastasis after surgical removal or primary melanoma in human patients

Enhancement of APC Activity  GM-CSF (Granulocyte-macrophage colony- stimulating factor) remember: CSFs are cytokines that induce the formation of distinct hematopoietic cell lines  Fig 22.11b

Cytokine Therapy  Use of recombinant cytokines (singly or in combination) to augment an immune response against cancer  Via isolation and cloning of various cytokine genes such as:  IFN-α, β, and γ  Interleukin 1, 2, 4, 5, and 12  GM-CSF and Tumor necrosis factor (TNF)

Cytokine Therapy Cont. I. Interferons Most clinical trials involve IFN-α Most clinical trials involve IFN-α Has been shown to induce tumor regression in Has been shown to induce tumor regression in hematologic malignancies i.e. leukemias, hematologic malignancies i.e. leukemias, lymphomas, melanomas and breast cancer lymphomas, melanomas and breast cancer All types of IFN increase MHC I expression All types of IFN increase MHC I expression IFN-γ also has also been shown to increase MHC IFN-γ also has also been shown to increase MHC II expressionon macrophages and increase II expressionon macrophages and increase activity of Tc cells, macrophages, and NKs activity of Tc cells, macrophages, and NKs

Cytokine Therapy Cont. II.Tumor Necrosis Factors Kills some tumor cells Kills some tumor cells Reduces proliferation of tumor cells without Reduces proliferation of tumor cells without affecting normal cells affecting normal cellsHow? Hemorrhagic necrosis and regression, inhibits Hemorrhagic necrosis and regression, inhibits tumor induced vascularization (angio-genesis) tumor induced vascularization (angio-genesis) by damaging vascular endothelium

Cytokine Therapy Cont. III.In Vitro-Activited LAK & TIL cells A. Lymphocytes are activated against tumor A. Lymphocytes are activated against tumor antigens in vitro antigens in vitro Cultured with x-irradiated tumor cells in Cultured with x-irradiated tumor cells in presence of IL-2 presence of IL-2 Generated lymphokine activated killer Generated lymphokine activated killer cells (LAKs), which kill tumor cells cells (LAKs), which kill tumor cells without affecting normal cells without affecting normal cells

In Vitro-Activated LAK and TIF cells Cont. B. Tumors contain lymphocytes that have infiltrated tumor and act in anti-tumor response via biopsy, obtained cells and via biopsy, obtained cells and expanded population in vitro with expanded population in vitro with generated tumor-infiltrating lympho- generated tumor-infiltrating lympho- cytes (TILs) cytes (TILs)

Monoclonal Antibodies Anti-idiotype Anti-idiotype Growth Factors Growth Factors-HER2 Immunotoxins Immunotoxins

Cancer Vaccines Genetic Genetic  Biochemical

HPV Human Papilloma Virus  E6  E7

From Normal to Abnormal:

For more info  HPV HPV  Cancer Vaccines Cancer Vaccines Cancer Vaccines

This Day Has Been Brought to you By the Letter… C C is for Cancer!