immunobiology of cancer
TRANSCRIPT
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THE IMMUNOBIOLOGY OF CANCER
Diana Santos 172459Joana Paulo 172455
Instituto Superior TécnicoMestrado Integrado em Engenharia BiomédicaEngenharia Biomolecular e Celular
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Outline
Bibliography
Hepatocelular Cancer
Immunosurveillance and Immunoediting
Innate and Adaptive Immunity
Cancer and its causes
Immunotherapy
Conclusion
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Cancer Cellular proliferation in an uncontrolled way;
Reproduction and no differentiation;
Invasion of adjacent tissues and possible spread in the body – metastasis.
Benign ones
They are not capable of metastasis: they do not kill the host
cells
Tumors
Malign ones
They grow indefinitely and
spread, leading to metastasis
CANCER
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Cancer Causes
External Factors leadingto cancer development
Carcinogenic Substances
UV and X Radiation
GeneticFactors
ViralInfections
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Proto-Oncogenes:
They promote the cell growthThey turn the replication process possible
WHEN MUTATED -Oncogenes
Oncogenes: •Increase on transcription factors•Transcription factors receptor’s activation•Signal molecules mutation•Increase on the expression of anti-apoptotic genes
CANCER
Tumor suppressing genes:They can induce apoptosis or delay the cell cycle, in order to have DNA reparation and to prevent uncontrolled cell replication
WHEN MUTATED
Cancer Causes
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What’s Cancer
Cell Growth
BLA
BLA
BLA
BLA
Cancer’s Etiology
Growth Promoting
Growth Restricting
Proto-oncogenes
Tumor supressor
genes
Growth Promoting
Growth Restricting
Mutations
Cancer Causes
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Innate and Adaptive Immunity
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Innate and Adaptive Immunity
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Immunosurveillance
• 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);
Lewis Thom as and Macfarlane Burnett
Unless there is a mechanism that allows tumor cells to evade from IS action, cancers would always be rejected
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What’s Cancer
BLA
BLA
Tumor & Immunology
BLA
BLA
BLA
Anti-tumor Immunosurveillance evidence
Micro tumors have a high incidence rate than cancers do;
Many cancers present in their composition immune cells;
Tumors are more frequent in immunodeficient patients;
Transplanted patients, who made immunosupressor treatments present a higher incidence of tumors;
Cancer is more likely to appear in advanced ages, when the immune system is lesser effective;
In some cases, in immunocompetent people, it is possible to occurs a regression of the tumor;
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Immunoediting
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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
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How can tumor cells avoid the Immunosurveillance?
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• 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
Hepatocellular Carcinoma (HCC)
Hepatitis B Virus (HBV)
Implicate as the probable causes oh HCC in at least 80% of cases worldwide
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Immune response against HCCCD4+
CD8+
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16
Cell Type Mechanism
CD4+ T cells Deletion of helper CD4+ T cell
CD8+ T cells Exhaustion of CD8+ T cellsUpregulation of PD-1Reduced CD28 and CD3 ExpressionIncrease caspase-3 activity
DCs Reduced IL-12 production
Kupffer Cells Increased PD-L1 expression
MDSCs Induction of TregSuppression of NK cell numbers
Neutrophils Induction of angiogenesis
NK Cells Reduced NK cell numbersImpaired NK cell Cytotoxicity
TAM Induction of Treg and TC17/Th17 cells
TC17/Th17 cells Induction of angiogenesis by IL-17 production
Failure mechanisms of immune responses against HCC
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How can we take advantage from immunobiologic response?
Immunotherapy
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Administration of monoclonal antibodies which target either tumour-specific or over-expressed antigens.
Apoptosis induction
Complement-mediated
cytotoxicity
ADCC
NKMØ
Conjugated to toxin / isotope
Passive Immunotherapy
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Vaccination strategies
Cell based Cytokines
• IL-2 • IFNs• TNFα
• Single peptide
• Multiple peptides
• HSP complexes
•Tumour-specific CTL
•Tumour-derived APC
•DC priming
Active Immunotherapy
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Effective Therapies
Regression of a large liver metastasis from kidney cancer in a patient treated with IL-2.
Regression is ongoing seven years later
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Conclusions
Immune system plays a surveillance role in controlling the development of cancer
Cancer development requires that malign cells escape from the immune system action, trough a set of mechanisms
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• 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." Langenbeck's Archives of Surgery: 1-8.
ConclusionsBibliography
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Questions
“It would be as difficult to reject the right ear and leave the left ear intact, as it is to immunize against cancer”.
W.H.Woglom, Cancer Research (1929)