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Immunobiology of cancer

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  • 1. InsCtuto  Superior  Técnico  Mestrado  Integrado  em  Engenharia  Biomédica  Engenharia  Biomolecular  e  Celular   THE  IMMUNOBIOLOGY  OF  CANCER   Diana  Santos  72459   Joana  Paulo  72455  
  • 2. Outline   Cancer  and  its  causes     Innate  and  Adap9ve  Immunity   Immunosurveillance  and  Immunoedi9ng   Hepatocelular  Cancer   Immunotherapy   Conclusion  Bibliography  
  • 3. Cancer  v  Cellular  proliferaCon  in  an  uncontrolled  way;  v  ReproducCon  and  no  differenCaCon;  v  Invasion  of  adjacent  Cssues  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  
  • 4. Cancer  Causes   External Factors leading to cancer development    Carcinogenic   UV  and  X   Gene9c   Viral      Substances   Radia9on   Factors   Infec9ons      
  • 5. Cancer  Causes   Tumor  suppressing   Oncogenes:     genes:   • Increase  on   They  can  induce   transcripCon  factors   apoptosis  or  delay  the   Proto-­‐Oncogenes:   • TranscripCon  factors   cell  cycle,  in  order  to     receptor’s  acCvaCon   have  DNA  reparaCon  They  promote  the  cell   • Signal  molecules   and  to  prevent  growth   mutaCon   uncontrolled  cell  They  turn  the   • Increase  on  the   replicaCon  replicaCon  process   expression  of  anC-­‐ WHEN  MUTATED  possible     apoptoCc  genes     CANCER   WHEN  MUTATED  -­‐ Oncogenes    
  • 6. Cancer  Causes   Muta9ons   Growth   Promo9ng   Growth  Restric9ng  
  • 7. Innate  and  AdapCve  Immunity  
  • 8. Immunosurveillance  Lewis  Thom  as  and  Macfarlane  BurneM   •  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);   Unless  there  is  a  mechanism  that  allows  tumor  cells  to  evade  from   immune  system  ac9on,  cancers  would  always  be  rejected        
  • 9. Ø  An9-­‐tumor  Immunosurveillance  evidence   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;  
  • 10. ImmunoediCng  Dunn,  G.  P.,  L.  J.  Old,  et  al.  (2004).    
  • 11. 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    
  • 12. Ø  How  can  tumor  cells  avoid  the   Immunosurveillance?   Theresa  L,  W.  (2006)  
  • 13. Hepatocellular  Carcinoma  (HCC)  •  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   Hepatitis B Virus (HBV) probable  causes  of  HCC  in   at  least  80%  of  cases   worldwide  
  • 14. Ø Immune  response  against  HCC   CD4+   CD8+  •  Flecken,  T.,  H.  Spangenberg,  et  al.  (2011)  
  • 15. Ø  Failure  mechanisms  of  immune   responses  against  HCC   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  
  • 16. How  can  we  take  advantage  from   immunobiologic  response?   Immunotherapy  
  • 17. Ø  Passive  Immunotherapy   AdministraCon  of  monoclonal  anCbodies  which  target   either  tumour-­‐specific  or  over-­‐expressed  anCgens.   MØ NKApoptosis Complemented ADCC Conjugated toinduction cytotoxicity toxin / isotope
  • 18. Ø  Ac9ve  Immunotherapy   •  Single peptide Vaccination •  Multiple peptides strategies   •  HSP Complex Cell Cytokines   based   • Tumour-specific CTL •  IL-2 • Tumour-derived APC •  IFNs •  TNFα   • Dendritc Cells
  • 19. 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)
  • 20. 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.   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)  
  • 21. 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  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."  Langenbecks  Archives  of  Surgery:  1-­‐8.  •  Copland  et  al  (2005)  Cancer  Immunol.  Immunother.  54:297  
  • 22. Thanks  for  your  aoenCon!  Questions