Cancer Immunology Introduction Ags expressed by cancer cells
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Cancer Immunology Introduction Ags expressed by cancer cells

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Cancer Immunology Introduction Ags expressed by cancer cells Cancer Immunology Introduction Ags expressed by cancer cells Presentation Transcript

  • Cancer Immunology
    • 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 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.
  • Types of Cancer
    • Carcinoma : Cancer of endo or ectoderm e.g. Skin or epithelial lining of organs
    • Sarcomas : Cancer of mesoderm e.g. bone
    • Leukemias and Lymphomas : Cancers of hematopoietic cells
    View slide
  • Cell Growth Control of cell growth Growth-promoting Proto-oncogenes Growth-restricting Tumor-suppressor genes View slide
  • Molecular Basis of Cancer Uncontrolled cell growth Proto-oncogenes Tumor-suppressor genes Mutations Radiation Chemicals Virus
  • Do tumors express foreign Ags? Transfer tumor H-2 k H-2 b Rejects tumor
  • Summary
    • When a tumor from H-2 k mouse was injected into H-2 b mouse, it was rejected.
    • This experiment does not demonstrate immunity against cancer.
    • Tumor was rejected due to expression of foreign MHC
  • Syngeneic (accepted) Allogeneic (rejected) Inbred : repeated brother-sister matings Outbred : normal population Xenogeneic (rejected)
  • Ags expressed on tumor cells Major Histocompatability Complex antigens TAVA TSTA TADA TSTA: unique to a tumor plays an important role in tumor rejection. Tumor-specific transplantation Ag Tumor associated developmental Ag Tumor associated viral Ag
  • Demonstration of TSTA Induce tumors with chemicals (carcinogens) e.g. methylcholanthrene, benzopyrene No tumor growth control tumor grows Remove tumor, irradiate and inject into syngeneic mice Inject viable tumor cells into normal or immunized mice Immunized mouse
  • Summary
    • Mice immunized with syngeneic irradiated tumor cells could reject the same live tumor upon rechallenge.
    • However, an unimmunized mouse developed tumor and died.
    • Because this experiment was done in a syngeneic mouse, tumors express TSTA.
  • Chemically induced cancers
    • Each tumor induced by a carcinogen expresses a unique Ag.
    • Thus difficult to develop vaccine.
  • 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
    • Silent gene-encoded Ags e.g. Thymic leukemic antigen (Tla) expressed in thymocytes of some strains
    • Differentiation Ags: B cells produce surface Ig.
      • B cell tumors have sIg
    • Melanomas and melanocytes express MART-1
    • Overexpression of Ag on tumors compared to normal cells e.g. In Breast cancer, HER2/neu homologous to Epidermal Growth Factor Receptor (EGFR)
    • Abnormal posttranslational modifications. Underglycosylated mucin (MUC-1) e.g. breast cancer
    • Ags expressed on male germ cells (lack MHC) and melanoma e.g. MAGE-1
  • Virally induced tumors
    • Types:
    • DNA viruses: papova (SV40, polyoma, papilloma), hepatitis, adenovirus.
    • RNA viruses: Retroviruses---> Human T-lymphotropic viruses (HTLV-I and HTLV-II).
    • Induce a strong immune response.
  • Feline leukemia Latent or recovered Oncogenic disease Non-oncogenic disease
  • Feline leukemia Virus
    • Transmitted from cat to cat through saliva or transplacentally
    • Cats produce virus neutralizing Abs and /or anti-tumor Abs
    • If both Abs are produced, cats recover.
    • If only anti-tumor Abs are produced, they get non-oncogenic disease.
    • If both Abs are not produced, cats get oncogenic disease.
  • UV-induced tumors
    • >800,000 cases of skin cancer/year.
    • UV radiation--->most serious skin cancer--->melanomas
    • Highly immunogenic.
  • Summary
    • A tumor grows in syngeneic host but not in allogeneic or xenogeneic hosts
    • Tumor Ags expressed may be specific to a tumor cell or shared with other cells
  • Evidence for the role of immune system in tumor rejection
    • Spontaneous regression
    • Regression of metastases after removal of primary tumor
    • Regression after chemotherapy
    • Infiltration of tumors by lymphocytes and macrophages
    • Lymphocyte proliferation in draining lymph nodes
    • Higher incidence of cancer after immunosuppression, immunodeficiency (AIDS, neonates), aging, etc.
  • Requirements for effective immune response against tumors
    • Tumor should express a foreign Ag.
    • Tumor should be immunogenic.
    • Host should be immunocompetent.
    • Immune response should not result in tolerance.
    • Tumor should not change Ag.
  • Immunity against tumors tumor macrophage T helper (Th) cell B cell
  • tumor CTL tumor Ag Class I MHC NK
  • FasL Fas CTL Tumor Perforin/ granzyme NK Apoptosis
  • T lymphocytes CD4 CD8 T helper T cytotoxic Tumor Tumor ClassI MHC ClassII MHC Ag Ag
    • Produce factors that
    • activate other cells to
    • kill tumor cells
    • Directly kill Cl II+ tumor cells
    Lyse tumor cells T cell receptor (TCR)
  • Role of CTL
    • TSTA is processed and presented with Class I MHC to CTL
    • CTL produce FasL or perforin/granzyme which kills the tumor cell.
    • If tumor cells are Fas+ve, CTL will use FasL to kill tumor cell apoptosis.
  • Role of Th cells
    • TSTA shed by cancer cells, is processed and presented by B cells or macrophages to Th cells
    • Th cells will activate B cells or macrophages by producing cytokines.
    • Abs are not very effective against cancer except against retrovirally induced tumors.
    • Activated macrophages can kill the tumor cells.
  • B Lymphocytes sIg Tumor Complement Natural Killer cell/ Macrophage/ Granulocyte FcR Fab Fc Tumor Ab dependent cell cytotoxicity(ADCC) Ag
  • Role of NK cells
    • NK cells can recognize MHC -ve tumor
    • NK cells are large granular lymphocytes (LGL) TCR - , asialoGM + or NK1.1 + .
    • It is not known exactly how NK cells recognize tumor cells.
    • Lyse virally-infected cells and tumor cells
    • Spontaneous cytotoxicity/ADCC
    • Activity increased by interleukin (IL)-2 = lymphokine-activated killer cells (LAK)
    • They use FasL and perforin to kill tumor cells.
  • Macrophages
    • Normal M  not tumoricidal
    • Activated M  are tumoricidal
    • Direct cytotoxicity or ADCC
    • Reactive oxygen intermediates (O - , H 2 O 2 )
    • Nitric oxide (NO)
    • Tumor necrosis factor (TNF)
    • Lysosomal enzymes
    • Antigen processing and presentation
  • How does a tumor escape immune recognition?
    • Generation of suppressor cells
    • Secrete immunosuppressive molecules
    • Ex: prostaglandins, transforming growth factor beta (TGF-  ), IL-10, etc.
    T regulatory M  CTL Tumor
    • Tumors may fail to process and present Ag.
    • Downregulation of MHC expression on tumor cell (CTL resistant but NK sensitive)
    • Tumors may fail to express adhesion/costimulatory molecules involved in T cell activation.
  • Tumors escape the action of CTL by not expressing B7 molecule involved in T cell activation tumor CTL tumor Ag Class I MHC B7 CD28
  • Tumor escape mechanisms: Fas FasL Tumor CTL Fas FasL Tumor CTL When tumor cells express Fas Ligand, they can kill Fas + T cells, thereby escaping immune destruction.
    • Ag masking : sialic acid, mucin, fibrin coating
    • Tolerance of host to tumor Ags - Neonatal exposure e.g. murine mammary tumor virus
    • Tolerogenic Ags of tumor (high dose/low dose or no costimulators)
    Tumor
    • Mutation in tumor cells with loss of antigen expression
    • Antigenic modulation : Ab binding leads to endocytosis or shedding of Ag-Ab complexes.
    • Blocking Factors : Shed Ag or Ag-Ab complexes act as blocking factors . Block FcR of NK or induce suppressor cells
  • Cancer Therapy
    • Surgery -
      • Localized tumors
    • Radiation -
      • Metastastic tumors
      • Affects proliferating cells (bone marrow, etc.)
      • Radiation-resistant tumors develop
    • Chemotherapy -
      • Metastastic tumors
      • Affects proliferating cells (bone marrow, etc.)
      • Drug-resistant tumors develop
    • Immunotherapy -
      • Metastastic tumors
      • Specificity
      • Do not develop resistance
      • No toxicity
  • Immunotherapy
    • Active Immunization :
      • Specific
        • Vaccination with viral Ags: e.g.
          • Feline leukemia virus (FLV)
          • Herpes - Marek’s disease of chickens
          • Hepatitis B virus.
        • Haptenated tumor cells (trinitrophenol - TNP)
        • Costimulator (B7) transfected tumor cells
  • tumor CTL CD28 Tumors escape the action of CTL by not expressing B7 molecule tumor B7 CD28 CTL No killing killing Use of B7 to induce anti-tumor immunity
  • B7-ve tumor Dies Survives tumor B7+ve tumor
  • Use of MAGE as a vaccine against melanomas
    • Expressed on normal melanocytes and melanomas – Vitiligo (skin depigmentation)
    MAGE
    • Nonspecific :
      • BCG (Bacillus Calmette-Guerin) Mycobacteria - melanoma, bladder carcinoma
      • Corynebacterium parvum (C. parvum)
      • Muramyl dipeptide
    Normal M  Tumor Activated M  Tumor lysis
      • Anti-CD3 Abs - polyclonal activation of T cells
    CD3 TCR Tumor T cell T cell Tumor CD3 TCR Tumor Ag MHC MHC Tumor Ag Anti-CD3 T cell Activation
    • Passive Immunization
      • Specific: Ab Therapy
        • Anti-idiotypic Abs
        • 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)
    B cell tumor Idiotype B cell IL-2R IL-2 Anti-IL-2R
  • Monoclonal Abs used in Immunotherapy
    • Unlabelled Ab: e.g. Anti-CD20 Ab in non-Hodgkin’s lymphoma
      • C’
      • ADCC
    • Labelled Ab (Radioisotope/Toxin)
      • 131 I (Iodine)
      • Internalization
    • Anti-tumor Abs coupled to toxin, radioisotopes, drugs or enzymes :
    • Immunotoxins :
    • Ricin A/diphtheria/Pseudomonas toxin coupled to Abs. e.g. antiCD22-Psudomonas toxin in hairy (B) cell leukemia
    • Toxin inhibits protein synthesis.
    • Cytocidal isotopes or anticancer drugs (adriamycin) coupled to Abs
    Tumor Ricin Prodrug Drug Ab-Enzyme
  • Inefficacy of Abs
    • Tumor Ags + Class I MHC
    • Shedding/internalization of tumor Ag/Ag-Ab complexes
    • Noncytotoxic Abs (C’/ADCC)
    • Anti-rat/mouse Ab develops causing anaphylaxis and serum sickness
      • – Humanized/chimeric Ab (from 2 species)
    Human Fc Mouse Fab Bispecific Ab Humanized Ab T cell Tumor cell CD3 Ag
    • Half life of Ab
    • Non specific binding to FcR+ cells (M  , granulocytes, NK and B cells)
    M 
  • Adoptive Immunotherapy 1. Lymphokine-activated killer cells (LAK): PBL + high dose IL-2 NK LAK 2. Tumor-infiltrating lymphocytes (TIL): In and around solid tumors Activated NK and CTL
  • 1)Use of LAK cells + IL-2 to treat cancer Isolate lymphocytes from blood lymphocytes +IL-2 for 3 days IL-2 LAK cells melanoma Immunotherapy of Cancer
  • Treatment of Melanoma with LAK cells +IL-2 Before After
  • 2) Use of tumor-infiltrating lymphocytes + IL-2 to treat cancer surgical removal of cancer nodule tumor T cell +IL-2 IL-2 Successful treatment of melanoma and renal cell carcinoma
  • Treatment of Melanomas with TIL + IL-2 Before After
  • Problems associated with IL-2 therapy
    • Very toxic----triggers vascular leak.
    IL-2 T cell CD44 endothelial cells
  • Dendritic Cells
    • Highly potent antigen processing and presenting cells
    • Prime an Immune Response
    • Pulse with tumor Ags or gene transfer
    Cl II Cl I
    • Autologous bone marrow (treated in vitro with Ab + C) transplantation following irradiation.
    • Allogeneic bone marrow transplantation (matching 1 or 2 HLA Ag) – Graft versus host reaction
  • Cytokine Therapy Inj. 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 IL-4 2. Tumor necrosis factor (TNF) - Carcinoma
  • 3. Interferon (IFN)-  Produced by Leukocytes Activates NK activity Increases class I MHC Hairy cell leukemia, renal cell carcinoma, melanoma, Kaposi sarcoma, hematologic cancers 4. IFN-  : Ovarian carcinoma 5. Hematopoietic growth factors: Overcome neutropenia Granulocyte-macrophage colony stimulating factor (GM-CSF) Granulocyte colony stimulating factor (G-CSF)
  • Gene therapy Introduce cytokine genes for IL-2, IL-4, IL-12, GM-CSF or IFN-  into tumor cells. Tumor Ag gene expressed in DC (Tumor Ag usually not known). tumor T cell M  IL-2 IL-4 GM-CSF
  • SUMMARY
    • Tumors should express TSTA.
    • T cells 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.
  • Immunotherapy of Cancer
    • Manipulation of the host’s immune system to treat cancer.
    • Treatment with IL-2---to activate NK/LAK cells.
    • Culture and transfer of tumor infiltrating lymphocytes.
    • Immunotoxins
    • Cytokine gene-therapy
    • Dendritic cell therapy
    • Bone marrow transplantation
    • Anti -idiotypic Abs against myelomas.
  • Suggested Reading
    • Immunobiology: The Immune System in Health and Disease by Janeway et al. 6 th edition, 2005. Pg. 630-642