1 / 62

Cancer Immunology

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.

libitha
Download Presentation

Cancer Immunology

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Cancer Immunology Introduction Ags expressed by cancer cells Nature of immune response How cancer evades immune system Immunotherapy

  2. 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.

  3. 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

  4. Cell Growth Control of cell growth Growth-restricting Tumor-suppressor genes Growth-promoting Proto-oncogenes

  5. Molecular Basis of Cancer Radiation Chemicals Virus Mutations Uncontrolled cell growth Proto-oncogenes Tumor-suppressor genes

  6. Do tumors express foreign Ags? tumor Transfer H-2k H-2b Rejects tumor

  7. Summary • When a tumor from H-2k mouse was injected into H-2b mouse, it was rejected. • This experiment does not demonstrate immunity against cancer. • Tumor was rejected due to expression of foreign MHC

  8. Inbred: repeated brother-sister matings Syngeneic (accepted) Outbred: normal population Allogeneic (rejected) Xenogeneic (rejected)

  9. Ags expressed on tumor cells Major Histocompatability Complex antigens Tumor-specific transplantation Ag TSTA TADA Tumor associated developmental Ag TAVA Tumor associated viral Ag TSTA: unique to a tumor plays an important role in tumor rejection.

  10. Demonstration of TSTA Induce tumors with chemicals (carcinogens) e.g. methylcholanthrene, benzopyrene control Inject viable tumor cells into normal or immunized mice Remove tumor, irradiate and inject into syngeneic mice tumor grows No tumor growth Immunized mouse

  11. 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.

  12. Chemically induced cancers • Each tumor induced by a carcinogen expresses a unique Ag. • Thus difficult to develop vaccine.

  13. 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

  14. 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

  15. 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.

  16. Feline leukemia Oncogenic disease Latent or recovered Non-oncogenic disease

  17. 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.

  18. UV-induced tumors • >800,000 cases of skin cancer/year. • UV radiation--->most serious skin cancer--->melanomas • Highly immunogenic.

  19. 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

  20. 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.

  21. 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.

  22. macrophage tumor B cell T helper (Th) cell Immunity against tumors

  23. tumor Class I MHC tumor Ag NK CTL

  24. Fas FasL Tumor Apoptosis CTL Perforin/ granzyme NK

  25. T lymphocytes T cell receptor (TCR) ClassII MHC ClassI MHC CD4 CD8 Tumor Tumor Ag Ag T helper T cytotoxic • Produce factors that activate other cells to • kill tumor cells • Directly kill Cl II+ tumor cells Lyse tumor cells

  26. 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.

  27. 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.

  28. B Lymphocytes Ag Tumor Natural Killer cell/ Macrophage/ Granulocyte Complement sIg Tumor Fc Fab FcR Ab dependent cell cytotoxicity(ADCC)

  29. 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.

  30. Macrophages • Normal Mf not tumoricidal • Activated Mf are tumoricidal • Direct cytotoxicity or ADCC • Reactive oxygen intermediates (O-, H2O2) • Nitric oxide (NO) • Tumor necrosis factor (TNF) • Lysosomal enzymes • Antigen processing and presentation

  31. Tumor How does a tumor escape immune recognition? • Generation of suppressor cells • Secrete immunosuppressive molecules Ex: prostaglandins, transforming growth factor beta (TGF-b), IL-10, etc. MF CTL T regulatory

  32. 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.

  33. tumor Class I MHC B7 CD28 tumor Ag CTL Tumors escape the action of CTL by not expressing B7 molecule involved in T cell activation

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

  35. Tumor • 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)

  36. 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

  37. 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

  38. 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

  39. Use of B7 to induce anti-tumor immunity CD28 tumor No killing CTL B7 CD28 killing tumor CTL Tumors escape the action of CTL by not expressing B7 molecule

  40. B7+ve tumor tumor B7-ve tumor Dies Survives

  41. MAGE Use of MAGE as a vaccine against melanomas Expressed on normal melanocytes and melanomas – Vitiligo (skin depigmentation)

  42. Nonspecific: • BCG (Bacillus Calmette-Guerin) Mycobacteria - melanoma, bladder carcinoma • Corynebacterium parvum (C. parvum) • Muramyl dipeptide Normal Mf Tumor Tumor lysis Activated Mf

  43. CD3 CD3 MHC • Anti-CD3 Abs - polyclonal activation of T cells MHC T cell Tumor T cell Tumor TCR TCR Tumor Ag Tumor Ag T cell Activation Anti-CD3

  44. Idiotype B cell tumor B cell 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) IL-2R Anti-IL-2R IL-2

  45. Monoclonal Abs used in Immunotherapy • Unlabelled Ab: e.g. Anti-CD20 Ab in non-Hodgkin’s lymphoma • C’ • ADCC • Labelled Ab (Radioisotope/Toxin) • 131I (Iodine) • Internalization

  46. Tumor Ricin 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 Prodrug Ab-Enzyme Drug

  47. Ag CD3 Tumor cell T cell 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) Bispecific Ab Humanized Ab Mouse Fab Human Fc

  48. Mf Half life of Ab Non specific binding to FcR+ cells (Mf, granulocytes, NK and B cells)

  49. 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

  50. Immunotherapy of Cancer 1)Use of LAK cells + IL-2 to treat cancer IL-2 Isolate lymphocytes from blood lymphocytes melanoma +IL-2 for 3 days LAK cells

More Related