TUMOR-IMMUNITÄT A.K. Abbas, A.H. Lichtman, S. Pillai (6th edition, 2007) Cellular and Molecular Immunology Saunders Elsevier Chapter 17, immunity to tumors
Immune surveillance hypothesis (Macfarlane Burnet, 1950s) importance still controversial but: it is clear that immune system reacts against tumor cells one of the factors in growth of malignant tumors: ability to evade or overcome mechanisms of host defense increased incidence of some tumor types in immunocompromized experimental animals and humans immune mechanisms can be exploited to destroy tumors
Expermental evidence: Methylcholantrene(MCA) -induced tumors
Tumor antigens: Tumor-specific: TSA Oncogenic mutants of normal cellular genes: ras, bcr-abl, p53 Randomly mutated genes: TSTA s (tumor-specific transplantation antigens) Can be identified: biochemical cdna cloning Tumor-associated: TAA Normal cellular proteins aberrantly expressed Tyrosinase - melanomas (enzyme melanin biosynthesis) Cancer/testis antigens: expressed testis and trophopblasts Oncofetal antigens: developing fetal tissue CEA: carcinoembryonic antigen - colon and many cancers, AFP: α-fetoptotein - hepatocellular cancer and others not specific, can be induced inflammatory conditions Altered glycolipid and glycoprotein antigens: gangliosides - in melanomas Mucin-1 - O-linked carbohydrates Tissue-specific differentiation antigens
Antigens of oncogenic viruses: DNA-viruses: EBV: Epstein-Barr HPV: papilloma Animals: Papovaviruses: SV40, polyoma Adenoviruses RNA viruses: Animal models In humans only HTLV-1 known: ATL, infects CD4+ cells
Tumor antigens recognized by T cells
Immune responses to tumors Innate: NK: MHC low, ligands for activating receptors (MICA, B, ULBP) LAK cells (IL2) Macrophages: direct by receptors? IFN-γ from T lymphocytes Adaptive: CD8+ cells: Clear for carcinogen-induced and virus-induced tumors Less clear for spontaneous But: tumor-specific CTL can be isolated from tumors Cross-presentation by professional APCs necessary to differentiate CD8+ cells to antitumor CTLs Use of pulsed DCs in tumor therapy CD4+ cells: not so clear Cytokines for CTL development TNF and IFN-γ - macrophage activation Antibodies: complement, Fc receptor (macrophages, NK) Little evidence for in vivo effective humoral response
Evasion of immune responses: Induction of tolerance by TA: MMTV SV40T transgenic Anergy induction by presentation by APC inducing tolerance Regulatory T cells: found in tumors Loss of antigen expression MHC downregulation Failure to induce CTL: no costimulators or MHCII Products suppressing immune response: TGF-β Fas-L masking of cell surface: sialic acid containing mucopolysaccharides
Immunotherapies Stimulation of active immune response Vaccination: Killed tumor vaccines + adjuvants Purified tumor antigens Pulsed DCs Cytokines and co-stimulator enhanced vaccines DNA vaccines Viral vectors: tumor antigens + cytokines Preventive versus therapeutic: hepatitis B HPV Augmentation by costimulators: B7 transfected tumor cells and cytokines: Il2, IL4, IFNs, GMCSF, TNF, IL12 Blocking inhibitory pathways: CTLA4 (autoimmunity!) Bacillus Calmette-Guerin Anti-CD3
Passive immunotherapies: LAK: from PBLs, IL2 In mice impressive effects In patients wide individual variation TILs: from inflammatory infiltrate, trials ongoing Graft versus leukemia effect Anti-tumor antibodies - humanized Anti-CD30 Anti-HER2 Coupled to toxins: ricin, diphteria toxin Radioisotopes Anti-tumor drugs Anti-EGF: colorectal cancer Anti-VEGF: in combination with chemotherapeutic agents Anti-tumor antibodies used to clear tumor cells from bone marrow Before autologous BM transplantation
Role of immune system in promoting tumor growth: Innate immune system: inflammation Macrophages (angiogenesis, tissue remodeling, free radicals/mutations) Gastric cancer by Heliobacter pylori Hepatocellular carcinoma by hepatitis B and C virus