Macrophages (M), or other APCs such as DCs, take up material from necrotic tumor cells. Next, they become activated and present epitopes derived from (tumor-associated antigens)TAAs on their respective MHC class I and class II molecules. Subsequently tumor-specific CD4+ helper T cells (TH) are activated and support the activation of CD8+ cytotoxic T cells (TC). Activated TC are able to lyse tumor cells that present the respective epitope on their MHC class I molecules. NK cells can lyse tumor cells directly or upon encounter of antibodies specific for antigens on the surface of tumor cells. The latter process is termed antibody-dependent cellular cytotoxicity (ADCC). Antibodies specific for TAAs are produced by B cells. Cytokines secreted by NKT cells and TH modulate the activity of TC and NK cells as well as the class switch of B cellsBiblio:
The mechanisms leading to an impairment of the immune response against HCC are summarized in Table 1. Taken together, many pathways have been shown to contribute to the apparent failure of the immune system in HCC. Further research is needed to better understand this failure and eventually be able to overcome it.
Instituto Superior TécnicoMestrado Integrado em Engenharia BiomédicaEngenharia Biomolecular e Celular THE IMMUNOBIOLOGY OF CANCER Diana Santos 172459 Joana Paulo 172455
OutlineCancer and its causes Innate and Adaptive Immunity Immunosurveillance and Immunoediting Hepatocelular Cancer Immunotherapy ConclusionBibliography
Cancer Cellular proliferation in an uncontrolled way; Reproduction and no differentiation; Invasion of adjacent tissues and possible spread in the body – metastasis. Tumors Benign ones Malign ones They are not capable They grow of metastasis: they indefinitely and do not kill the host spread, leading to cells metastasis CANCER
Cancer Causes External Factors leading to cancer developmentCarcinogenic UV and X Genetic Viral Substances Radiation Factors Infections
Cancer Causes Tumor suppressing Oncogenes: genes: •Increase on They can induce transcription factors apoptosis or delay the Proto-Oncogenes: •Transcription factors cell cycle, in order to receptor’s activation have DNA reparationThey promote the cell •Signal molecules and to preventgrowth mutation uncontrolled cellThey turn the •Increase on the replicationreplication process expression of anti- WHEN MUTATEDpossible apoptotic genes CANCER WHEN MUTATED - Oncogenes
What’s Cancer Causes Cancer Cancer’s EtiologyCell Growth Mutations BLA BLA Growth BLA Promoting BLA Growth Restricting
ImmunosurveillanceLewis Thom as and Macfarlane Burnett • IS is continuously able to supervise the organism and to distinguish between tumor cells and others; • Tumor cells are immunogenic and distinct from others (antigenically);Unless there is a mechanism that allows tumor cells to evade from IS action, cancers would always be rejected
Anti-tumor What’s Cancer Immunosurveillance evidence BLA Micro tumors have a high incidence rate than cancers do; BLA Many cancers present in their composition immune cells; Tumor &Immunology Tumors are more frequent in immunodeficient patients; BLA Transplanted patients, who made immunosupressor treatments present a higher incidence of tumors; BLA Cancer is more likely to appear in advanced ages, when the immune BLA system is lesser effective; In some cases, in immunocompetent people, it is possible to occurs a regression of the tumor;
How can tumor cells avoid the Immunosurveillance? Immunologic tolerance (negative selection of T cells) Immunosupressor cytokines (IL-10, TGF-β1, TGF-α) Loss/Down-regulation of MHC-I molecules Immunosuppressive cells (T regulatory cells, NKT cells) T and NK cells apoptosis due to FasL high expression levels, by tumor cells
How can tumor cells avoid the Immunosurveillance?
Hepatocellular Carcinoma (HCC)• Primary liver cancer is the fifth most common cancer in the world and the third most common cause of cancer mortality• Hepatocellular carcinomas (HCCs) are malignant tumors of liver parenchymal cells Hepatitis B Virus (HBV) Implicate as the probable causes oh HCC in at least 80% of cases worldwide
Failure mechanisms of immune responses against HCC Cell Type Mechanism CD4+ T cells Deletion of helper CD4+ T cell CD8+ T cells Exhaustion of CD8+ T cells Upregulation of PD-1 Reduced CD28 and CD3 Expression Increase caspase-3 activity DCs Reduced IL-12 production Kupffer Cells Increased PD-L1 expression MDSCs Induction of Treg Suppression of NK cell numbers Neutrophils Induction of angiogenesis NK Cells Reduced NK cell numbers Impaired NK cell Cytotoxicity TAM Induction of Treg and TC17/Th17 cells TC17/Th17 cells Induction of angiogenesis by IL-17 production 16
How can we take advantage from immunobiologic response? Immunotherapy
Passive Immunotherapy Administration of monoclonal antibodies which target either tumour-specific or over-expressed antigens. MØ NKApoptosis Complement- ADCC Conjugated toinduction mediated toxin / isotope cytotoxicity
Active Immunotherapy • Single peptide Vaccination • Multiple peptides strategies • HSP complexes Cell Cytokines based •Tumour-specific CTL • IL-2 •Tumour-derived APC • IFNs • TNFα •DC priming
Effective Therapies Regression of a large liver metastasis from kidney cancer in a patient treated with IL-2. Regression is ongoing seven years later
ConclusionsImmune system plays a surveillance role in controlling thedevelopment of cancer Cancer development requires that malign cells escape from the immune system action, trough a set of mechanisms
Bibliography Conclusions• Visser, K. E., A. Eichten, et al. (2006). "Paradoxical roles of the immune system during cancer development." Nat Rev Cancer 6(1): 24-37.• Theresa L, W. (2006). "Immune suppression in cancer: Effects on immune cells, mechanisms and future therapeutic intervention." Seminars in Cancer Biology 16(1): 3-15.• Leon, K., K. Garcia, et al. (2007). "How Regulatory CD25+CD4+ T Cells Impinge on Tumor Immunobiology: The Differential Response of Tumors to Therapies." The Journal of Immunology 179(9): 5659-5668.• Rosenberg (2001) Nature, 411;381-4• El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557–2576.• Spangenberg HC, Thimme R, Blum HE (2009) Targeted therapy for hepatocellular carcinoma. Gastroenterology 6 (7):423–432.• Flecken, T., H. Spangenberg, et al. (2011) "Immunobiology of hepatocellular carcinoma." Langenbecks Archives of Surgery: 1-8.
QuestionsW.H.Woglom, Cancer Research (1929) “It would be as difficult to reject the right ear and leave the left ear intact, as it is to immunize against cancer”.