Introduction to TUMOR IMMUNOLOGY

TUMOR IMMUNOLOGY Tumor recognition is a complex, challenging problem for the immune system, which must distinguish proper cellular growth and organization from neoplastic transformation. This process involves -recognition of tumor antigens by effector cells and -response of organ against tumor, -induction of immunity Tumor antigens Many neoplastic cells produce antigens -Antigens are in the bloodstream or -Remain on the cell surface The key role of the immune system is detection of the tumor Ags The immune rsponse to tumor antigens varies and Often insufficient to prevent tumor growth Developing of tumor cell=genetic modification ONKOGEN ACTIVATION Secunder messenger transcription activators cell cycles genes Tissue cells growth inhibitor transcription receptors Fas gene Malignant cells TUMOR SZUPPRESSZOR INAKTIVATION DNA repair enzimes AQUIRATED CHARACTERISTICS DEVELOPING OF TUMOR CELLS TUMORGENESIS: MORE GENES ARE INVOLVED 1. Alteration of oncogenes: mutations, will be antigens, new functions, generate a novel protein sequence 2. Alterations of tumor suppressor genes, , wich are normally not expressed or are expressed very low (ras, p53) 3. Induction of new genetic information from virus ( eg, HPV E6, E7 proteins in cervical cancer, 4. Abnormally high accumulation of proteins that normally are present at lower levels (eg, prostate- specific antigens, melanoma associated antigens 5. Release of antigens normally sequestred within the cells or is organelles when neoplastic cells die. Tumorantigens Tumor specific antigens (TSA) are unique to tumor cells. Tumor-specific mutations that generate unique epitopes New antigens, these are only in the tumor cells p53 caspase 8 CDK4 adeno cc head and neck melanoma Tumor-associated antigens are relatively restricted to tumor cells Ag-s overexpressed by tumor cells compared to normal tissue Melan-A melanoma HER-2/neu (growth factor R) breast, Ovarium telomerase The effector mechanism: CTL Alteration of oncogenes: mutations, will be antigens, new functions, generate a novel protein sequence Tumor-testis antigens (tumor specific Ag-s) Non-mutated ‘self’ antigens that are found only in testis Tumorantigens Alteration of oncogenes: mutations, will be antigens, new functions, -generate a novel protein sequence DNA HPVE6 Papova, Herpes, Papilloma HPVE7 RNA virus Retrovirus, HTLV HIV, HHV8 Oncofoetal proteins: CEA APF Tissue specific diff. antigens: CALLA/CD10 EBV/LMP2 ENV/EBNA colorectal tumor hepaocelular cc leukemia Tumor-testis antigens (tumor specific Ag-s) Non-mutated ‘self’ antigens that are found only in testis - The immune system is capable of recognizing and responding to tumor antigens The tumors have complet Ag structures The effector mechanism are different Protect the organ can tolerate the tumor Mechanism against the tumors Innate immunity •Natural killer cell (NK) tumoricid activity NK: CD16R (IgG binding R) CD56 adhesion molecule Cytokine binding R (IL-2) •NKT cell line (T cell marker- TCR, CD3+) •Antibody-dependent killer cell (ADCC) • Activated macrophages - (lymphokines produced by T cells) • DC cells- take up tumor associated proteins – process them, and present T cells to stimulate the CTL response against tumor Mechanism against the tumors Adaptive immunity Cytotoxic T cells (CTL-CD8+ T cells) direct lysis of tumor cells Delayed type hypersensitivity (DTH) CD4+ T cells help the CTL production activation migration to tumor antibody production by B cells Mo, NK cell activation Lymphokine activated killer cells (LAK cells) Humoral mechanism Role of T cells in the anti-tumor immune response Tumor Ag 1. Tumor cells – MHCI + Effector mechanism CD8+ T cell (cytotoxic) tumor lysis or tolerance 2. APC-tumor Ag + MHCII+ CD4+ T cell 1. Tumor cell present Ag-s to T cells as peptide fragments on the surface of MHC molecules. In the absence of co-stimulatory signals, tolerance may result. 2. Tumor Ag-s are taken up by antigen presenting cells, which can present peptide fragments to both CD4+ and CD8+ cells become cytotoxic and are then able to lyse tumor cells. Activated CD4+ T cells produce Cytokines- IL2, GM- CSF B cell activation Mo- NK cell activation Memory CD4+T cells Tumor cell present Ag-s to T cells as peptide fragments on the surface of MHC molecules. In the absence of co-stimulatory signals, tolerance may result. IL-2, GM-CSF) B cell activation Mo-NK activity DC CD4+T cell 40 LAPC cell- CD40 R Adhevise mlecule expression + costimulators- CD80- CD86 Tumor Ag-s are taken up by antigen presenting cells Prevention of tumor cells Therapy against the tumor ACTIVE PASSIVE increasing the self immunoreactivity the patients receiveantibody or cellular components Passive immunotherapy Lymphokin-activated killer cells (LAK) no evidence of benefit • TIL = tumor infiltrating lymphocytes + in vitro IL-2 stimulation • Results: 10-20% (melanoma, renal tumor) or Activated LAK Activated TIL + in vivo IL-2 Side effect: cytokine release syndrome, capillary leak syndrome, lung and brain oedema 2. Tumor specific cytotoxic T cell allogenic bone marrow transplantation – my developed e.g. EBV associated lymphoma Treatment: Donor specific T cells (EBV sensitive cytotoxic T cells) to recipient (clonally reactive T cells) may provide clinical benefit 3. Stem cell therapy a/After chemotherapy bone marrow deficiency peripheral stem cell pool allograft or autograft b/ Hematopoetic malignancies graft bone marrow T cells or peripheral T cells damage normal tissue Ag + the tumor cells 4. HSP therapy HSP was obtained from tumor (hsp70, hsp90, grp94/pg96) HSP adjuvant, and binding the tumor protein – increase the T cell response 5. EBV associated tumors EB-V--- B cell transformation EBV associated tumors: immunoblastic lymphoma nasopharyngeal cc Hodgkin disease Virus membrane Ag components into the recipient – develop antiviral antibody (CTL -CD8+ T) lyses the tumor cells Humoral responses to cancer Human r MAB against tumor Ag-s Therapy: MAB binding to tumor Ag Mechanism: - ADCC - Complement activation - R-binding – apoptosis B cell lymphoma (MAB- CD19,CD20,CD37,HLA-DR, CD52) Anti-CD-20 (Rituximab) T cell lymphoma Anti-CD25 cutaneous T cell lymphoma Diagnostic: Therapeutic: Isotope labelled MAB-s - detect the tumor, or Toxic effect – I131, Y40 Anti-Tumor MAB Avastin (bevacizumab) VEGF BEXXAR (tositumomab)CD20 Campath (alemtuzumab) CD52 Herceptin (Trastuzumab) Rituxan (Rituximab) CD20 metastatic colorectal tu, non small cell lung tumor NHL B cell CLL Metastatic breast tumor NHL Zamyl CD33 Zevalin (itritumomab) CD20 AML NHL Bispecific antibodies Effector cells (TCR) Bispec. AB Target cell (tumor- Fcg R) Release Cytotoxic mediators, perforine, granzyme Cytokines Fas ligand secretionResults- target (tumor cell) lyses Active immunization Vaccine therapy: clinical trial under way Tumors vaccine Autolog vaccine Must know tumor associated Ag-s or peptid epitopes allogenic vaccine Anti-idiotipic vaccineautologous (lymphoma) If the cancer associated peptid Ag is unknown vaccination with irradiated or lyses tumor Ag Immunotherapy DC Vaccination Need peptide which contains tumor epitop DC vaccination: MNC obtained from tumor + (GM-CSF+IL-4) – DC cells Differentiation Activation Proliferacion + autologous tumor Ag (epitop) (CD8+ CD4+ T cells are activated Cytokines used as adjuvants for immunotherapy Cytokines IL-2 IL-4 Activity helper signal for CD8+ T cells, bypassing T cell help enhances the activity of some NK clones Promotes maturation and enhanced antigen presentation of DC cells IL-12 GM-CSF IFN-gamma Acts with IL-2 t induce differentiation of CD8+ cells Up-regulates expression of MHC-I and MHCII and costimulator molecules Activates macrophages, NK cells and B cells induces differentiation of B cells Serum tumor markers Marker CEA Carcinoembrionális Antigen AFP Alpha-Fetoprotein CA 19-9 Carbohydrate-Antigen 19-9 Pancreas CA 15-3 Cancer-antigen 15-3 CA 125 Cancer-Antigen 125 PSA Prostata Specific Antigen NSE Neuron-Specific Enolase SCC Sqamosus Cell Carcinoma Calcitonin HCG Human Chorio Gonadothropin Trophoblast TPA Tissue Polypeptide Antigen Human Thyroglobulin CA 72-4 2 microglobulin Screen C-cell Liver Pancreas Prognosis Breast, Colon, Lung Liver Breast Ovarium Prostata Lung Cervix, C-cell Throphoblast Thyroid Gastric, ovarium Myeloma multiplex Prostata Lung C-cell Trophoblast MM Known tumour antigens and associated tumours Tumor specific AGS (tumor-testis Ag) MAGE-1, MAGE-2 MAGE-3 MAGE-12 RAGE-1 GAGE-1 and 2 NY-ESO-1 Melanoma, lung, bladder and others Melanoma, lung, bladder, head, neck Melanoma Renal, sarcoma, bladder, melanoma, mesothelioma Melanoma, sarcoma, lung, bladder, head, neck Melanoma, breast, prostate, bladder Mutated or unique tumor antigens -Catenin Melanoma, gastric Intest. carboxyl esterase Kidney CDK4 Melanoma Caspase 8 Head and neck p53 Adeno cc Other antigens Telemerase SART-1 PRAME RU2 Multiple tumors Squamosus cc (lung and esophagus) Melanoma, lung, sarcoma Kidney, multiple organs Known tumour antigens and associated tumours Tumor antigens 5. Viral tumor antigens Burkitt lymphoma Nasopharingeal cc Anal cc Human papilloma virus (HPC-E6/7) – cervix cc T cell leukemia Human T lymphotropic virus (HTLV) Hepatitis B Hepatitis C Hepatoma Cytokines used as adjuvants for immunotherapy