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Tumour immunology
- 1. tumor immunology 1interactive immunology CANCER AND THE IMMUNE SYSTEM Prof. dr. Milan Taradi, M.D. PhD Department of Physiology and Immunology
- 2. tumor immunology Taradi 2Interactive immunology Objectives Oncology, prevalence Definition, origin, classification, clonal nature Tumor growth, vasculatization, necrosis, metastasis, heterogeneity Cellular changes, carcinogenesis, oncogens, mutation, tumor supressor genes, viruses Tumor immunology, antigens, response to tumor, tumor escape mechanisms Immunotherapy, imunodiagnosis, immunoprophylaxis
- 3. tumor immunology Taradi 3Interactive immunology Oncology Oncology is the branch of medicine (biology) that deals with tumors. Tumor, which means swelling, neoplasm which means new growth and cancer which means spreading in the menner of a crab are synonym. Cancer cells are altered self-cells that have escaped normal growth regulating mechanisms.
- 4. tumor immunology Taradi 4Interactive immunology Prevalence Current estimates project that one person in three will develop cancer, and that one in five will die from it. Cancer is the second-ranking cause of death, led only by cardiovascular disease. Cancer is largely a disease of older people.
- 5. tumor immunology Taradi 5Interactive immunology Origin of the tumour In most tissues of a mature organism, a balance is maintained between cell renewal and cell death. Occasionally, though, cells arise that no longer respond to normal growth-control mechanisms. These cells give rise to clones of cells that can expand to a considerable size, producing a tumour, or neoplasm.
- 6. tumor immunology Taradi 6Interactive immunology Benign and Malignant Tumour A tumour that grows incapsulated and does not invade the healthy surrounding tissue is benign. A tumour that grows uncontrolled invasive, progressive, destructive and that exhibit metastasis is malignant.
- 7. tumor immunology Taradi 7Interactive immunology Classification of tumours Malignant tumours or cancers are classified according to the embryonic origin of the tissue from which the tumour is derived. – Carcinomas are tumors that arise from endodermal or ectodermal tissues such as skin or the epithelial lining of internal organs and glands. – Sarcomas arise from mesodermal connective tissues such as bone, fat, and cartilage. – Leukemia, lymphoma and myeloma are malignant tumors of hematopoietic cells of the bone marrow.
- 8. tumor immunology Taradi 8Interactive immunology The Clonal origin of tumour Tumour is a clon of cells. Tumours are monoclonal at the time of initiation. Most tumours exhibit genomic instability such that additional genetic abnormalities accumulate during the course of the disease and frequently correlate with clinical aggressiveness.
- 9. tumor immunology Taradi 9Interactive immunology The Characteristics of Transformed Cells Altered antigen expression (mutant antigens, virally controled antigens, loss of MHC class I expresion) Altered surface charge Altered surface carbohydrate expression Altered nuclear/cytoplasmic ratio Altered and variable nuclear morphology (pleomorphism) Altered nuclear staining (hyperchromasia) Altered DNA content (aneuploidy) Molecular alterations in key regulatory genes (expression of normally silent genes) Molecules related to metastatic potential (CD44) Reduced requirements for growth factors (or serum) when grown in vitro Growth at very low cell densities in vitro Loss of contact inhibition (ie. still proliferate at high densities) Growth in an anchorage independent manner Immortality: ie. do not show senescence after 70 rounds of division (ie. they exceed Hayflick limit) Tumourigenesis in animal models
- 10. tumor immunology Taradi 10Interactive immunology Induction of Cancer: A Multistep Process The development from a normal cell to a cancerous cell is usually a multistep process of clonal evolution driven by a series of somatic mutations that progressively convert the cell from – normal growth to a – precancerous state and finally into a – cancerous state.
- 11. tumor immunology Taradi 11Interactive immunology Induction of Cancer: A Multistep Process Development of Colon Cancer
- 12. tumor immunology Taradi 12Interactive immunology Tumour vascularisation The angiogenesis is required for tumors to grow beyond 1 mm in size.
- 13. tumor immunology Taradi 13Interactive immunology Tumor neovasulature abnormalities Tumor vasulature abnormalities lead to the shutdown of blood supply to the tumor cells and essentially starving it to death.
- 14. tumor immunology Taradi 14Interactive immunology Tumour Necrosis and Hypoxia
- 15. tumor immunology Taradi 15Interactive immunology Tumour growth and metastasis (a) A single cell develops altered growth properties at a tissue site.
- 16. tumor immunology Taradi 16Interactive immunology Tumour growth and metastasis (b) The altered cell proliferates, forming a mass of localized tumor cells, or benign tumor.
- 17. tumor immunology Taradi 17Interactive immunology Tumour growth and metastasis (c) The tumour cells become progressively more invasive, invading the underlying basal lamina.
- 18. tumor immunology Taradi 18Interactive immunology Tumour growth and metastasis (d) The malignant tumor metastasizes by generating small clusters of cancer cells that dislodge from the tumor and are carried by the blood or lymph to other sites in the body.
- 19. tumor immunology Taradi 19Interactive immunology Tumour growth and metastasis Binding Digestion Motility
- 20. tumor immunology Taradi 20Interactive immunology Proliferation and Growth of Tumours Tumours are characterised by invasion into nearby tissues and structures and may spread to distant sites (metastasis).
- 21. tumor immunology Taradi 21Interactive immunology Malignant Transformation of Cells Induction of Cancer: A Multistep Process Growth of brest cancer
- 22. tumor immunology Taradi 22Interactive immunology Tumour Heterogeneity Tumours are generally composed of subpopulations of cells that are heterogeneous for many characteristics such as: – morphology, – karyotype, – antigenicity, – immunogenicity, – biochemical properties, – growth rate, – metastatic potential, – sensitivity to chemotherapeutic agents, – sensitivity to radiation etc. The leading hypothesis for the origin of tumour subpopulations is the genetic and epigenetic instability of cancer cells. Tumour heterogeneity is a fundamental property of cancer and has important biological and clinical consequences among which augmentation of tumour progression and development of resistance to treatment are most crucial for the host.
- 23. tumor immunology Taradi 23Interactive immunology The Cell Cycle At the two major checkpoint of the cell cycle the cell decides whether to commit itself to the complete cycle.
- 24. tumor immunology Taradi 24Interactive immunology The Cell Cycle Representative schematic of the two major checkpoint of the cell cycle. Immortality is acquired at chromosome’s ends. One characteristic of DNA replication is that the ends of linear DNA molecules are progressively shortened at each round of replication of normal cells, but not in tumour cells.
- 25. tumor immunology Taradi 25Interactive immunology Regulation of Cell Growth
- 26. tumor immunology Taradi 26Interactive immunology Cancer-Associated Genes Cancer associated genes can be divided into three categories: – Genes that induce cellular proliferation • Growth factors • Growth-factor receptors • Signal transducers • Transcription factors – Tumour-suppressor genes • Rb, suppressor of retinoblastoma • P53 encodes a nuclear phosphoprotein – Genes that regulate programmed cell death • bcl - 2, an anti-apoptosis gene
- 27. tumor immunology Taradi 27Interactive immunology Oncogenes and Cancer Induction Proto-oncogenes encode proteins involved in control of normal cellular growth. The conversion of proto- oncogenes to oncogenes is one of the key steps in the induction of most human cancer. This conversion may result from mutation in an oncogene, its translocation, or its amplification.
- 28. tumor immunology Taradi 29Interactive immunology Oncogenes and Cancer Induction Viral oncogens Cellular oncogens
- 29. tumor immunology Taradi 30Interactive immunology Chromosome translocations In the past 30 years, molecular pathology (which includes chemistry, biochemistry, molecular biology, molecular virology, molecular genetics, epigenetics, genomics, proteomics, and other molecular- based approaches) has identified some key alterations that are required for cellular transformation and malignancy. Chromosome translocations are common in lymphoproliferative disorders. A hallmark of human chronic myeloid leukaemia is a 9;22 chromosome translocation that generates the so- called ‘Phyladelphia chromosome’. 'Phyladelphia chromosome'
- 30. tumor immunology Taradi 31Interactive immunology Gene expression profiles Schematic representation of the test technology used to determine the expression status of the 70 gene profile or signature that is indicative of a poor prognosis.
- 31. tumor immunology Taradi 32Interactive immunology Burkit's Lymphoma It is endemic in central Africa, where it is the commonest childhood malignancy and is strongly associated with Epstein-Barr virus infection. c-myc
- 32. tumor immunology Taradi 33Interactive immunology Multimodal Therapy The tumour load should be reduced by: – Surgery – Irradiation – Chemotherapy – Immunotherapy – Thermotherapy – Genes therapy
- 33. tumor immunology Taradi 34Interactive immunology Tumour antigens The tumour antigens recognized by human T cells fall into one of four major categories: – Antigens encoded by genes specifically expressed by tumors – Antigens encoded by variant forms of normal genes that have been altered by mutation – Antigens normally expressed only at certain stages of differentiation or only by certain differentiation lineages – Antigens that are overexpressed in particular tumors
- 34. tumor immunology Taradi 35Interactive immunology Tumour antigens Mutation (new) Inappropriate expression (embryonic) Overexpression (normal)
- 35. tumor immunology Taradi 36Interactive immunology Tumour Antigens Tumour cells display – tumour-specific antigens (TSA) and the more common – tumour-associated antigens (TAA). Tumour-specific antigens are unique to tumour cells and do not occur on normal cells in the body. Tumour-associated antigens, which are not unique to tumour cells, may be proteins that are expressed on normal cells during fetal development, but that normally are not expressed in the adult.
- 36. tumor immunology Taradi 37Interactive immunology Tumour Transplantation Antigens Two types of tumour transplantation antigens have been identified on tumour cells: – tumour-specific transplantation antigens (TSTAs) – and tumour-associated transplantation antigens (TATAs).
- 37. tumor immunology Taradi 38Interactive immunology Oncogenes and Cancer Induction Conversion of proto- oncogenes into oncogenes can involve – mutation, resulting in production of qualitatively different gene products, or – DNA amplification or – translocation, resulting in increased or decreased expression of gene products.
- 38. tumor immunology Taradi 39Interactive immunology Virally controlled antigens After infection with oncogenic viruses, they express genes homologous with cellular oncogens which encode factors affecting growth and cell division.
- 39. tumor immunology Taradi 40Interactive immunology The Immune Response to Tumours Immune surveillance against strongly immunogenic tumours – Cell-mediated responses to tumours – Humoral responses to tumours Immunological escape of tumours – Immunological unresponsiveness – Immunoselection (“sneaking through”) – Antigen modulation – Immunological enhancement and blocking antibody – Circulating antigen, immune complex – Shedding of antigens (“antgenic smokescreen”) – Immunologically privileged sites
- 40. tumor immunology Taradi 41Interactive immunology Immune Response to Tumours The immune response to tumors includes – CTL-mediated lysis, – NK-cell activity, – macrophage- mediated tumor destruction, and – destruction mediated by ADCC.
- 41. tumor immunology Taradi 42Interactive immunology Melanoma cells and macrophages
- 42. tumor immunology Taradi 43Interactive immunology Tumor Evasion of the Immune System Tumors may evade the immune response by – modulating their tumor antigens – reducing their expression of class I MHC molecules – antibody-mediated or immune complex- mediated inhibition of CTL activity.
- 43. tumor immunology Taradi 44Interactive immunology Tumour Escape Mechanisms
- 44. tumor immunology Taradi 45Interactive immunology Tumour Escape Down-regulation of class I MHC expression on tumour cells may allow a tumour to escape CTL mediated recognition.
- 45. tumor immunology Taradi 46Interactive immunology Cancer Immunotherapy Attack on tumour cells – Antigen-independent • Interleukin treatment • Interferon therapy • Colony-stimulating factors • Heat-shock proteins immunization – Antigen- dependent • Immunization with tumour antigens (peptides or whole tumour cells) • Therapy with monoclonal antibodies (linked with killer molecule, “magic bullets”, radioimmunotherapy ) • Vaccination against oncogenic viruses Attack on the tumour blood supply – Vascular Endothelial Growth Factor (VEGF) is a potent angiogenic growth factor.
- 46. tumor immunology Taradi 47Interactive immunology The History of Tumour Immunotherapy Old, 1996
- 47. tumor immunology Taradi 48Interactive immunology Vaccination Strategies Key elements in the design of strategies for vaccination against cancer are: – the identification of significant tumour antigens by genetic or biochemical approaches – the development of strategies for the effective presentation of tumour antigens and – the generation of activated populations of helper or cytotoxic T cells.
- 48. tumor immunology Taradi 49Interactive immunology Isolation of Tumour Peptides The method used to isolate tumor antigens that induce tumour-specific CTLs.
- 49. tumor immunology Taradi 50Interactive immunology Therapy with transfection
- 50. tumor immunology Taradi 51Interactive immunology Therapy with transfection Use of transfected tumor cells for cancer immunotherapy. Tumor cells transfected with the B7 gene express the co-stimulatory B7 molecule, enabling them to provide both activating signal (1) and co-stimulatory signal (2) to CTL
- 51. tumor immunology Taradi 52Interactive immunology Attack on the tumour blood supply The target for “magic bullets” – receptors for VEGF – oncofetal fibronectin – matrix metalloprotease – pericyte markers
- 52. tumor immunology Taradi 54Interactive immunology Cancer Immunodiagnosis Circulating and cellular tumour markers – alpha-fetoprotein, – carcinoembryonic antigens Tumour imaging – antibody imaging Detection of micrometastases – immunocytochemistry
- 53. tumor immunology Taradi 55Interactive immunology SUMMARY Tumour antigens The immune response to tumour Immunotherapy Immunodiagnosis Immunoprophylaxis
Editor's Notes
- Cancer is a diverse collection of diseases that are caused by abnormal and invasive cell proliferation.
- Cancer is one of the leading causes of death in humans with most cancer deaths resulting from local invasion and distant metastases of tumour cells. Treatment of the cancer at this stage of the progression of the disease has of course clear limitations. What is urgently needed is a detailed examination of all possibilities that might result in the reversal of the proliferation of cancer cells so that a much more efficient therapeutic regimen could be designed for cancer patients.
- _ _ _ This days the cancer occur frekvently than in earlier periods. Whay? The life expectancy and the average age of population are increasing.
- Carcinoma - Epithelial tissue cancers. Smooth linings of inner & outer surfaces of body. Sarcoma - Connective tissue involvement, bone, cartilage, and muscle. Leukemia - Cancers arising in the blood, stem cells in bone marrow. Lymphoma - Cancer of the lymphatic system. Carcinomas account for about 85% of all cancers. Another 10% are Sarcomas and Leukemias. Carcinoma rates increase with age. Sarcoma , which accounts for about 2% of cancers, has a constant rate across the lifespan
- Tumour instability can lead to resistance of the cancer cells to new target-based therapeutics.
- As eukaryotic cells divide, the protective ends of the linear chromosomes, the telomeres, gradually shorten with each cell division. When a critical telomere length is reached, the cells are signalled into senescence, an irreversible state of quiescence. Thus, telomere length has emerged as a replicative clock within each population of cells and the tissues and organs they form in vitro. Consequently telomere length has become accepted as a biomarker for biological ageing in vivo .
- Representative schematic of the two major checkpoint of the cell cycle and involvement of some of the major tumor suppressor gene products. The ATM and ATR kinases are involved in the signaling of DNA damage. These kinases phosphorylate a number of downstream mediators, including p53and Chk (Checkpoint kinases 1 and 2). Phosphorylation of p53activates this transcription factor that in turn promotes synthesis of p21WAF, which inhibits the cyclin/CDK complexes, thus activating the G1/S checkpoint. If DNA damage cannot be repaired, p53promote s apoptosis. p53is also involved in the establishment of the G2/M checkpoint. The tumor suppressor p16INK4A is involved in inhibition of CDKs, thus contributing to the G1/S checkpoint. The checkpoint kinases halt the cell cycle by phosphorylating (thus inactivating) cdc25 protein family members. Cdc25 are phosphatases that activated cdc2 complexed with cyclin B. The latter complex is the mytosis-promoting factor (MPF), which is the complex that regulates cell entry into the Mphase Immortality is acquired at chromosomes’ ends The ends of all eucaryotes’ chromosome are organized into structures termed telomeres. One characteristic of DNA replication is that the ends of linear DNA molecules are progressively shortened at each round of replication because DNA polymerase uses RNA primers that are degraded after elongation, a phenomenon known as ‘end replication problem’ Therefore, telomeres work as a cellular hour glass that determines how many replication rounds a cell can afford. The protein component of telomerase (TERT, the reverse transcriptase) is not expressed (or expressed at insufficient levels) in most somatic cells. For this reason, somatic cells cannot restore the length of telomeres during cell proliferation and undergo replicative senescence and crisis. As a result of mutations, or of viral infection in certain cells (Foddis et al., 2002), tumor cells regain sufficient amounts of TERT expression and thus can proliferate indefinitely.
- Immune cells in the tumour microenvironment not only fail to mount an effective anti-tumour immune response, but also interact intimately with the transformed cells to promote oncogenesis actively. Signal transducer and activator of transcription 3 (STAT3), which is a point of convergence for numerous oncogenic signalling pathways, is constitutively activated both in tumour cells and in immune cells in the tumour microenvironment. Constitutively activated STAT3 inhibits the expression of mediators necessary for immune activation against tumour cells. Furthermore, STAT3 activity promotes the production of immunosuppressive factors that activate STAT3 in diverse immune-cell subsets, altering gene-expression programmes and, thereby, restraining anti-tumour immune responses. As such, STAT3 propagates several levels of crosstalk between tumour cells and their immunological microenvironment, leading to tumour-induced immunosuppression. Consequently, STAT3 has emerged as a promising target for cancer immunotherapy.
- - - - Different mechanisms generate tumor-specific transplantation antigens (TSTAs) and tumor-associated transplantation antigens (TATAs). The latter are more common.
- - The immune response may play a role in selecting for tumor cells expressing lower levels of class I MHC molecules by preferentially eliminating those cells expressing high levels of class I molecules. With time, malignant tumor cells may express progressively fewer MHC molecules and thus escape CTL-mediated destruction.
- Most of the recent advances in cancer immunotherapy have involved the identification and targeting of key molecular drivers of the disease process. Antibodies can target toxins or radioactive isotopes to the tumor-cell surface.
- As a result of the combined signals, the CTL differentiate into effector CTLs, which can mediate tumor destruction. In effect, the transfected tumor cell acts as an antigen-presenting cell. (b) Transfection of tumor cells with the gene encoding GM-CSF allows the tumor cells to secrete high levels of GM-CSF. This cytokine will activate dendritic cells in the vicinity of the tumor, enabling the dendritic cells to present tumor antigens to both TH cells and CTL-Ps.