immunobiology of cancer
TRANSCRIPT
THE IMMUNOBIOLOGY OF CANCER
Diana Santos 72459 Joana Paulo 72455
InsCtuto Superior Técnico Mestrado Integrado em Engenharia Biomédica Engenharia Biomolecular e Celular
Bibliography
Hepatocelular Cancer
Immunosurveillance and Immunoedi9ng
Innate and Adap9ve Immunity
Cancer and its causes
Immunotherapy
Conclusion
Outline
v Cellular proliferaCon in an uncontrolled way;
v ReproducCon and no differenCaCon;
v Invasion of adjacent Cssues 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
Cancer
Cancer Causes
External Factors leading to cancer development
Carcinogenic Substances
UV and X Radia9on
Gene9c Factors
Viral Infec9ons
Proto-‐Oncogenes: They promote the cell growth They turn the replicaCon process possible
WHEN MUTATED -‐
Oncogenes
Oncogenes: • Increase on transcripCon factors • TranscripCon factors receptor’s acCvaCon • Signal molecules mutaCon • Increase on the expression of anC-‐apoptoCc genes
CANCER
Tumor suppressing genes: They can induce apoptosis or delay the cell cycle, in order to have DNA reparaCon and to prevent uncontrolled cell replicaCon
WHEN MUTATED
Cancer Causes
Growth Promo9ng
Growth Restric9ng
Muta9ons
Cancer Causes
Innate and AdapCve Immunity
• Immune System is conCnuously able to supervise the organism and to disCnguish between tumor cells and others;
• Tumor cells are immunogenic and disCnct from others (anCgenically);
Lewis Thom as and Macfarlane BurneM
Unless there is a mechanism that allows tumor cells to evade from immune system ac9on, cancers would always be rejected
Immunosurveillance
Micro tumors have a high incidence rate than cancers do;
Many cancers present in their composiCon immune cells;
Tumors are more frequent in immunodeficient paCents;
Transplanted paCents, 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 effecCve;
In some cases, in immunocompetent people, it is possible to occurs a regression of the tumor;
Ø An9-‐tumor Immunosurveillance evidence
ImmunoediCng
Dunn, G. P., L. J. Old, et al. (2004).
Ø How can tumor cells avoid the Immunosurveillance?
Immunologic tolerance (negaCve selecCon of T cells)
Immunosupressor cytokines (IL-‐10, TGF-‐β1, TGF-‐α)
Loss/Down-‐regulaCon 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
Ø How can tumor cells avoid the Immunosurveillance?
Theresa L, W. (2006)
• Hepatocellular carcinomas (HCCs) are malignant tumors of liver parenchymal cells
• Primary liver cancer is the fihh most common cancer in the world and the third most common cause of cancer mortality
Hepatocellular Carcinoma (HCC)
Hepatitis B Virus (HBV)
probable causes of HCC in at least 80% of cases worldwide
Ø Immune response against HCC CD4+
CD8+
• Flecken, T., H. Spangenberg, et al. (2011)
Cell Type Mechanism
CD4+ T cells DeleCon of helper CD4+ T cell
CD8+ T cells ExhausCon of CD8+ T cells UpregulaCon of PD-‐1 Reduced CD28 and CD3 Expression Increase caspase-‐3 acCvity
DCs Reduced IL-‐12 producCon
Kupffer Cells Increased PD-‐L1 expression
MDSCs InducCon of Treg Suppression of NK cell numbers
Neutrophils InducCon of angiogenesis
NK Cells Reduced NK cell numbers Impaired NK cell Cytotoxicity
TAM InducCon of Treg and TC17/Th17 cells
TC17/Th17 cells InducCon of angiogenesis by IL-‐17 producCon 15
Ø Failure mechanisms of immune responses against HCC
How can we take advantage from immunobiologic response?
Immunotherapy
AdministraCon of monoclonal anCbodies which target either tumour-‐specific or over-‐expressed anCgens.
Apoptosis induction
Complemented cytotoxicity
ADCC
NK MØ
Conjugated to toxin / isotope
Ø Passive Immunotherapy
Vaccination strategies
Cell based Cytokines
• IL-2 • IFNs • TNFα
• Single peptide
• Multiple peptides
• HSP Complex
• Tumour-specific CTL
• Tumour-derived APC
• Dendritc Cells
Ø Ac9ve Immunotherapy
Ø Effec9ve Therapies
Regression of a large liver metastasis from kidney cancer in a pa9ent treated with IL-‐2.
Regression is ongoing seven years later
Rosenberg (2001)
“It would be as difficult to reject the right ear and leave the leh ear intact, as it is to immunize against cancer”.
W.H.Woglom, Cancer Research (1929)
Conclusions
Immune system plays a surveillance role in controlling the development of cancer
Cancer development requires that malign cells escape from the immune system acCon, through a set of mechanisms
Tumors like HCC are globally increasing
Further research is needed to beoer understand failure mechanisms of immune systems and eventually be able to overcome it.
Conclusions Bibliography • 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 therapeuCc intervenCon." Seminars in Cancer Biology 16(1): 3-‐15.
• Dunn, G. P., L. J. Old, et al. (2004). "The Immunobiology of Cancer Immunosurveillance and ImmunoediCng." Immunity 21(2): 137-‐148.
• 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.
• Copland et al (2005) Cancer Immunol. Immunother. 54:297
Thanks for your aoenCon!
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