Post on 03-Jan-2016
transcript
Biological basis for immunotherapyin solid tumors
Licia Rivoltini, MDUnit of Immunotherapy of Human Tumors
Fondazione IRCCS Istituto Nazionale dei TumoriMilano
Perspectives in Lung Cancer: 16th European CongressTorino, March 6-7, 2015
Immune system in infectious disease
Referenze: A, Richard L. et al. PNAS, 2010 , vol. 107; B. Dr. Volker Brinkmann, Max Planck Institute for Infection Biology; C. http://pathmicro.med.sc.edu/ghaffar/innate.htm ;D. , http://www.lbl.gov/Science-Articles/Archive/PBD-immune-system.html; E. B cell Analytical Imaging Facility of the Albert Einstein College of Medicine and the NCI cancer center support grant (P30CA013330).
B lymphocytes T lymphocytes
phagocytes
natural killer cells
Cancer Immunosurveillance
Tumor cells
CD8+
phagocytes
CD4+
B cellsNK cells
The immune system recognitionand targeting of tumor cells
Cancer Immunology(ImmunOncology)
Understanding cancer immune evasion and researching avenues to
help the immune system controlling tumor growth
Innate immunity
Rapid, first-linenon specific immune response
Innate immunity
NK cellsrecognize
infected target cells
Infected cells Phagocytes(macrophages, dendritic cells)
engulf pathogens and dying
infected cells
Adaptive immunity
Specific immune responseImmunological memory
ANTIGENPRESENTIG
CELLS(dendritic cells)present
antigens from pathogens
Adaptive immunity
MHC-I
Activated CD8+cytotoxic T cells
ANTIGENPRESENTIG
CELLS(dendritic cells)present
antigens from pathogens
Adaptive immunity
MHC-ITCR
Infected host cellsActivated CD8+cytotoxic T cells
ANTIGENPRESENTIG
CELLS(dendritic cells)present
antigens from pathogens
Adaptive immunity
MHC-ITCR
Infected host cellsActivated CD8+cytotoxic T cells
ANTIGENPRESENTIG
CELLS(dendritic cells)present
antigens from pathogens
Activated B cells
Adaptive immunity
MHC-ITCR
T helper cellsCytokines
Infected host cellsActivated CD8+cytotoxic T cells
ANTIGENPRESENTIG
CELLS(dendritic cells)present
antigens from pathogens
Activated B cells
Adaptive immunity
MHC-ITCR
T helper cellsCytokines
Antibodiesagainst the pathogen
Immunological memory
Pathogen clearance
Immunological memory
Pathogen clearance
Activation of negative
feedback pathwaysto shut down immune
response
Immunesuppressive cells
Negativecheckpoints
Regulatory T cells
Myeloid derived suppressor cells
CTLA4PD1
Immunological memory
Pathogen clearance
Memory T cells and Ab
Immunesuppressive cells
Negativecheckpoints
Regulatory T cells
Myeloid derived suppressor cells
CTLA4PD1
Activation of negative
feedback pathwaysto shut down immune
response
Tumor cells express ANTIGENS that can be recognized by T cells
Infected host cells
CD8+ T cells
Tumor cells
CD8+ T cells
Pathogen proteins Proteins associatedwith cancer transformation
T cellreceptor
MHCclass I
Tumor Associated Antigens(TAA)
Tissue antigens(MUC1, EPCAM,PSA, PSMA,Mart-1, CEA….…)
Unique mutated antigens (cancer genetic instability)
Embryonic antigens(MAGE3, NY-ESO1, PRAME….)
Tumor draining lymph node
Tumor site
Tumor cell debris(ANTIGENS)
Mechanisms leading to spontaneous tumor immunity
Dendritic cells
CytokinesChemokines
NK cells
- PRIMING PHASE -
CD8+T cells
cytokines
YY
YYYY
B cells
CD4+ T cells
cytokines
Antibodies
Y Y
Y
Peripheral blood
Y Y
YTumor
growth control
- EFFECTOR PHASE -
Tumor Immunity
Cycle
Tumor cell
Activated CD8+cytotoxic T cells
(CTL)
Cytotoxicgranules
(perforin, granzyme B)
FasL Fas
Pathways of tumor cell killing by CD8+ T cells
TCR
MHC/Ag
Immunosurveillance in cancer patients
o Presence of antigen-specific T cells and antibodies at tumor site, draining LN and peripheral blood of cancer patients
Immunosurveillance in cancer patients
o Presence of antigen-specific T cells and antibodies at tumor site, draining LN and peripheral blood of cancer patients
o Tumor T cell infiltrate often associates with better prognosis
Immunosurveillance in cancer patients
o Presence of antigen-specific T cells and antibodies at tumor site, draining LN and peripheral blood of cancer patients
o Tumor T cell infiltrate often associates with better prognosis
o Immunosuppressive pathways increase with disease progression
Correlation with improved overall or progression-free survival, disease stage, or therapy outcome; type of lymphocyte dictates where there is a correlation with improved outcome
Figures adapted from Zhang L, et al. N Engl J Med 2003;348(3):203–213, Copyright ©2003 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 1. Zhang L, et al. N Engl J Med 2003;348(3):203–213; 2. Hiraoka K, et al. Br J Cancer 2006;94(2):275–280; 3. Galon J, et al. Science 2006;313(5795):1960–1964; 4. Mahmoud SM, et al. J Clin Oncol 2011;29(15):1949–1955; 5. Loi S, et al. J Clin Oncol 2013;31(7):860–867; 6. Piras F, et al. Cancer 2005;104(6):1246–1254; 7. Azimi F, et al. J Clin Oncol 2012;30(21):2678–2683 8. Siddiqui SA, et al. Clin Cancer Res 2007;13(7):2075–2081; 9. Donskov F, et al. Br J Cancer 2002;87(2):194–201; 10. Flammiger A, et al. APMIS 2012;120(11):901–908 11. Badoual C, et al. Clin Cancer Res 2006;12(2):465–472; 12. Piersma SJ, et al. Cancer Res 2007;67(1):354–361 , 13. Azimi et al., J Clin Oncol 2012
Al-Shibli et al., Clin Cancer Res 2008
Angell and Galon, Current Opin Immunol 2013
IMMUNOSCORE
T cell infiltrate is positive prognostic factor in several cancer histologies
Adaptive immunity in cancer patients
- role of T cell infiltrate -
NSCLC
Anti-tumor immune response
Tumor growth
Subclinical pre-diagnosis phase
ELIMINATIONOf tumor cells
(partial or complete)
Tumor immunity: a dynamic interaction
Anti-tumor immune response
Tumor growth
Subclinical pre-diagnosis phase
ELIMINATIONOf tumor cells
(partial or complete)
EQUILIBRIUMbetween
immune responseand tumor growth
Imm
unos
elec
tion/
editi
ng
Tumor immunity: a dynamic interaction
Anti-tumor immune response
Tumor growth
Subclinical pre-diagnosis phase Clinical phase
ELIMINATIONOf tumor cells
(partial or complete)
EQUILIBRIUMbetween
immune responseand tumor growth
ESCAPEof tumor cells
from immune control
Imm
unos
elec
tion/
editi
ng
Tumor immunity: a dynamic interaction
Tumor cells
Down-modulationof MHC or antigen
expression
Tumor immune escape mechanisms:tumor cells counterattack
Down-modulationof MHC or antigen
expression
Tumor cells
Up-regulation of pro-apoptotic molecules
(FasL, TRAIL)
Tumor immune escape mechanisms:tumor cells counterattack
Down-modulationof MHC or antigen
expression
Tumor cells
Up-regulation of pro-apoptotic molecules
(FasL, TRAIL)
Tumor immune escape mechanisms:tumor cells counterattack
Release of immune suppressive factors(TGFb, PG2, iNOS…)
Expression of inhibitory checkpoints (PDL1)
IneffectiveT cells
tumor cells T cells
RegulatoryT cells
Myeloid-derived suppressor cells
Immunesuppression
• Release of TGFb, iNOS, IDO• Expression of inhibitory
checkpoints(CTLA4, PD1, PDL1, LAG3, TIM3, BLTA)
Tumor immune escape mechanisms:switch-off of immune responses
To summarize
To summarize
• Spontaneous tumor immunity does occur in cancer patients (Tumor Immunity Circle)
To summarize
• Spontaneous tumor immunity does occur in cancer patients (Tumor Immunity Circle)
• T cell immunity contribute to better prognosis (Immunoscore)
To summarize
• Spontaneous tumor immunity does occur in cancer patients (Tumor Immunity Circle)
• T cell immunity contribute to better prognosis (Immunoscore)
• Tumor cells acquire the ability to evade immune recognition (Tumor Immune Escape)
Anti-tumor immune response
Tumor growth
ELIMINATIONOf tumor cells
(partial or complete)
ESCAPEof tumor cells
from immune control
EFFECTIVE IMMUNOTHERAPY
CANCER IMMUNOTHERAPY:tilt the balance to immune tumor control
Valeria BerettaChiara CastelliChiara CamisaschiAgata CovaPaola DehoPaola FratiSimona FrigerioFelicetta Giardino
German Cancer Research Center Heidelberg, Germany
Viktor UmanskyAlexandra Sevko
Unit of Melanoma Surgery
Mario SantinamiRoberto PatuzzoRoberta RuggeriAndrea MaurichiFrancesco Gallino
Department of Pathology
Gabrina TragniAntonello CabrasElena TamboriniFederica PerroneGiuseppe Pelosi
Unit of Immunotherapy of Human Tumors
Aldo BonoElena TolomioDaniele Moglia
Veronica HuberMonica RodolfoPaola SquarcinaMarcella TazzariViviana VallacchiElisabetta Vergani
Medical Oncology UnitINT Milan
Filippo de BraudLorenza Di GuardoMichele Del Vecchio
36
Acknowledgements
MIA Consortium, University of Milano Bicocca
Barbara VerganiAntonello Villa
Thank you