Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Perspectives in Lung Cancer: 16th European Congress Torino, March 6-7, 2015 Biological basis for immunotherapy in solid tumors Licia Rivoltini, MD Unit of Immunotherapy of Human Tumors Fondazione IRCCS Istituto Nazionale dei Tumori Milano 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). Cancer Immunosurveillance The immune system recognition and targeting of tumor cells phagocytes NK cells B cells CD4+ CD8+ Tumor cells Cancer Immunology (ImmunOncology) Understanding cancer immune evasion and researching avenues to help the immune system controlling tumor growth Innate immunity Rapid, first-line non specific immune response Innate immunity NK cells recognize infected target cells Infected cells Phagocytes (macrophages, dendritic cells) engulf pathogens and dying infected cells Adaptive immunity Specific immune response Immunological memory Adaptive immunity MHC-I ANTIGEN PRESENTIG CELLS(dendritic cells) present antigens from pathogens Adaptive immunity TCR MHC-I Activated CD8+ cytotoxic T cells ANTIGEN PRESENTIG CELLS(dendritic cells) present antigens from pathogens Adaptive immunity TCR MHC-I Activated CD8+ cytotoxic T cells ANTIGEN PRESENTIG CELLS(dendritic cells) present antigens from pathogens Infected host cells Adaptive immunity TCR MHC-I Activated CD8+ cytotoxic T cells ANTIGEN PRESENTIG T helper cells Cytokines CELLS(dendritic cells) present antigens from pathogens Activated B cells Infected host cells Adaptive immunity TCR MHC-I Activated CD8+ cytotoxic T cells ANTIGEN PRESENTIG Infected host cells T helper cells Cytokines CELLS(dendritic cells) present antigens from pathogens Activated B cells Antibodies against the pathogen Immunological memory Pathogen clearance Immunological memory Activation of Pathogen clearance negative feedback pathways to shut down immune response Immune suppressive cells Negative checkpoints CTLA4 PD1 Regulatory T cells Myeloid derived suppressor cells Immunological memory Activation of Pathogen clearance negative feedback pathways to shut down immune response Immune suppressive cells Memory T cells and Ab Negative checkpoints CTLA4 PD1 Regulatory T cells Myeloid derived suppressor cells Tumor cells express ANTIGENS that can be recognized by T cells CD8+ T cells CD8+ T cells MHC class I Infected host cells Pathogen proteins T cell receptor Tumor cells Proteins associated with cancer transformation Tumor Associated Antigens (TAA) Tissue antigens (MUC1, EPCAM, PSA, PSMA, Mart-1, CEA….…) Embryonic antigens (MAGE3, NY-ESO1, PRAME….) Unique mutated antigens (cancer genetic instability) Mechanisms leading to spontaneous tumor immunity - PRIMING PHASE Tumor draining lymph node Tumor Immunity Cycle Dendritic cells cytokines CD4+ T cells - EFFECTOR PHASE - Tumor site NK cells Cytokines Chemokines B cells cytokines Tumor cell debris (ANTIGENS) CD8+ T cells Tumor growth control Antibodies Peripheral blood Pathways of tumor cell killing by CD8+ T cells Cytotoxic granules (perforin, granzyme B) MHC/Ag TCR FasL Activated CD8+ cytotoxic T cells (CTL) Fas Tumor cell 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 Adaptive immunity in cancer patients - role of T cell infiltrate - T cell infiltrate is positive prognostic factor in several cancer histologies NSCLC IMMUNOSCORE Angell and Galon, Current Opin Immunol 2013 Al-Shibli et al., Clin Cancer Res 2008 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 Tumor immunity: a dynamic interaction ELIMINATION Of tumor cells (partial or complete) Subclinical pre-diagnosis phase Tumor growth Anti-tumor immune response Tumor immunity: a dynamic interaction ELIMINATION EQUILIBRIUM between immune response and tumor growth Immunoselection/editing Of tumor cells (partial or complete) Subclinical pre-diagnosis phase Tumor growth Anti-tumor immune response Tumor immunity: a dynamic interaction ELIMINATION EQUILIBRIUM between immune response and tumor growth ESCAPE of tumor cells from immune control Immunoselection/editing Of tumor cells (partial or complete) Subclinical pre-diagnosis phase Tumor growth Anti-tumor immune response Clinical phase Tumor immune escape mechanisms: tumor cells counterattack Tumor cells Down-modulation of MHC or antigen expression Tumor immune escape mechanisms: tumor cells counterattack Tumor cells Down-modulation of MHC or antigen expression Up-regulation of pro-apoptotic molecules (FasL, TRAIL) Tumor immune escape mechanisms: tumor cells counterattack Tumor cells Down-modulation of MHC or antigen expression Up-regulation of pro-apoptotic molecules (FasL, TRAIL) Expression of inhibitory checkpoints (PDL1) Release of immune suppressive factors (TGFb, PG2, iNOS…) Ineffective T cells Tumor immune escape mechanisms: switch-off of immune responses tumor cells T cells Immune suppression • Release of TGFb, iNOS, IDO • Expression of inhibitory checkpoints (CTLA4, PD1, PDL1, LAG3, TIM3, BLTA) Regulatory T cells Myeloid-derived suppressor cells 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) CANCER IMMUNOTHERAPY: tilt the balance to immune tumor control ELIMINATION Of tumor cells (partial or complete) ESCAPE of tumor cells from immune control Tumor growth Anti-tumor immune response EFFECTIVE IMMUNOTHERAPY Acknowledgements Unit of Immunotherapy of Human Tumors Valeria Beretta Chiara Castelli Chiara Camisaschi Agata Cova Paola Deho Paola Frati Simona Frigerio Felicetta Giardino Veronica Huber Monica Rodolfo Paola Squarcina Marcella Tazzari Viviana Vallacchi Elisabetta Vergani Unit of Melanoma Surgery Department of Pathology Mario Santinami Roberto Patuzzo Roberta Ruggeri Andrea Maurichi Francesco Gallino Gabrina Tragni Antonello Cabras Elena Tamborini Federica Perrone Giuseppe Pelosi Aldo Bono Elena Tolomio Daniele Moglia Medical Oncology Unit INT Milan Filippo de Braud Lorenza Di Guardo Michele Del Vecchio MIA Consortium, University of Milano Bicocca German Cancer Research Center Heidelberg, Germany Barbara Vergani Antonello Villa Viktor Umansky Alexandra Sevko 36 Thank you