Tumor Immunology

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Tumor Immunology
The ultimate goal of Tumor Immunology Induction
of clinically effective anti-tumor immune
responses in patients with pre-existing tumors
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Types of Cancer

• Carcinoma Cancer of endo or ectoderm e.g. Skin
  or epithelial lining of organs
• Sarcomas Cancer of mesoderm e.g. bone, muscles
• Leukemias and Lymphomas Cancers of hematopoietic
  cells

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Evidence for Immunologic Defenses Against Cancer
in Humans

• Immune cells around tumor mass
• Hyperplasia of local lymph node
• Increment of MHC class II and ICAM-1
• Immunodeficiency is associated with increased
  incidence of cancers - B-cell lymphomas
• AIDS
• Transplant patients

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The 10 leading Causes of Death in the US
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Tumor Immunology
Characterization of tumor antigens Immune
responses to tumors Evasion of tumor from
immunosurvillance Immunotherapy
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Immunologic Defenses Against Cancer in
Experimental Animals

• Tumors induced by the same virus express the same
  virally determined antigens
• Tumors induced by the same chemical are
  antigenically distinct
• If a tumor is removed from a mouse, and the mouse
  later re-injected with the same tumor cells, no
  tumor will form

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What are the Antigens Expressed on Tumors?

• Tumor Specific Antigens (TSA)
• Are only found on tumor cells.
• Arise due to point mutations or rearrangement of
  cellular genes.
• Can be derived from viral antigens of
  transforming viruses.
• Tumor Associated Antigens (TAA)
• Found on both normal and neoplastic tissue, but
  the expression is greatly altered/increased on
  cancer cells.
• Oncofetal antigens are developmental antigens
  which become derepressed. (CEA and AFP)
• Differentiation antigens are tissue specific.
• Altered modification of a protein could be an
  antigen.

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Tumor Immunity
-Tumors express antigens that are recognized as
foreign by the immune system of the
tumor-bearing host -Immune responses frequently
fail to prevent the growth of tumors -The immune
system can be stimulated to effectively kill
tumor cells and eradicate tumor
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Tumor Immunity
Innate Immunity Macrophage Natural killer
cells Adaptive Immunity CTLs Antibody
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Innate immune system I

• Macrophages
• are activated by IFN?
• kill target cells by releasing TNF?, radical
  oxygen species, NO, and proteases

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II

• Natural Killer Cells (NK cells)
• can mediate cytotoxicity of cells which have
  down-regulated their MHC I
• part of the innate immune system involved in
  immune surveillance
• mediate cytotoxicity by using perforin and
  granzymes, Fas L, and IFN?
• NK deficient animals have a higher incidence of
  neoplastic disease

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Innate Immunity NK cells
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Adaptive Immunity
Cell-mediated immunity CD8 CTLs Humoral
immunity Antibody activating complement ADCC
(macrophage, NK cell)
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Tumor Immunity
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The Humoral Immune SystemWhat role does it play?

• Antibodies may bind antigens on the tumor. This
  may result in
• complement fixation on the tumor cell
• antibody dependent cytotoxicity by NK cells,
  macrophages and CD8 killer T cells

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Antibody Effector Functions
Carter P., Nature Rev Cancer.20011118-130
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Mechanisms of Immunologic Cytotoxicity

• Macrophage-mediated cytotoxicity
• Natural killer cell-mediated cytotoxicity
• T cell-mediated cytotoxicity
• Antibody-dependent cell-mediated cytotoxicity
• Complement-mediated cytotoxicity

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How Does the Tumor Evade the Immune System?

• Low immunogenicity low expression of adhesion
  molecules, MHC, co-stimulatory molecules, tumor
  antigens
• Antigen the tumor may not express antigen
  against which the immune system is reactive.
  mutation of tumor antigens and antigen masking
• Immunosuppression tumor cells may make compounds
  that suppress immune cells (MHC class 1). TGF-b
• Speed of tumor growth may outpace the immune
  system
• Antigen released may saturate the TCRs of T
  cells or released immunoglobulins

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Cancer Immunotherapy

Active Immunotherapy Adjuvants Cancer
vaccines Cytokines Passive Immunotherapy Monoclo
nal antibodies In vitro-activated LAK
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Adjuvants
Inflammatory substances BCG (macrophage
activator) Polyclonal activators of
T-lymphocytes anti-CD3 antibody (low dose)
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Cancer Vaccines
Abbas,Lichtman and Pobber, Cellular and
Molecular Immunology. W.B. Saunders. 1999. Fig.
17-5
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Cytokines

• IL-2 ? increment of LAK and NK activity TNF, IL-1
  and IFN-gamma
• TNF toxic in high level
• IFN-alpha increment of NK activity and
  augmentation of MHC class I expression
• IFN-gamma increment of NK and macrophage
  activities and augmentation of MHC expression

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MHC Adenovirus- Induced Tumors
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Cancer Immunotherapy

Active Immunotherapy Adjuvants Cancer
vaccines Cytokines Passive Immunotherapy Monoclo
nal antibodies In vitro-activated LAK
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Monoclonal Antibodies
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Cancer Immunotherapy

Active Immunotherapy Adjuvants Cancer
vaccines Cytokines Passive Immunotherapy Monoclo
nal antibodies In vitro-activated LAK
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Treatment of Melanoma with LAK cells IL-2
Before
After