Pene_GrrrOH_02072015 - public [Mode de compatibilité]
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Impact de l’agression aiguë sur le pronostic du cancer Frédéric Pène Medical ICU, Hôpital Cochin, AP-HP, Paris, France Université Paris Descartes, Sorbonne Paris Cité Institut Cochin, Inserm U1016, CNRS UMR-8104 Groupe de Recherche Respiratoire sur la Réanimation en Onco-Hématologie (Grrr-OH) Survival to septic shock in cancer patients: the CUB-Réa network (n=3437) Mortality rate (%) P < 0.001 Hospital mortality ICU mortality 1997 1999 2001 2003 2005 2007 Year Zuber, Crit Care Med 2012 Cancer and infections: a complex crosstalk Increased susceptibility Cancer Infection Changes in host defence induced by malignancies and antineoplastic treatment Lehrnbecher, Lancet Oncol 2008 P. aeruginosa intratracheal instillation Fox, J Immunol, 2011 66C4 Non-cancer 4T1 Cancer and infections: a complex crosstalk Increased susceptibility Cancer Chronic infection / inflammation Infection Grivennikov, Cell 2010 Cancer and infections: a complex crosstalk Increased susceptibility Cancer Chronic infection / inflammation Infection Acute inflammation / sepsis? Nosocomial infections Adapted from Hotchkiss et al., Nat Med 2009 Bactéries / TLRs et croissance tumorale Effets cellulaires directs des bactéries ou TLRs Actions sur le microenvironnement tumoral Angiogénèse Perméabilité vasculaire Invasion tumorale Effets variables en fonction du stade tumoral Flagelline précoce: favorise la croissance tumorale Flagelline tardive: inhibe la croissance tumorale Rôle des TLRs dans la réponse immunitaire antitumorale induite par la chimiothérapie Huang Cancer Res 2007, Bohnhorst Leukemia 2006, Pidgeon Br J Cancer 1999, Harmey Int J Cancer 2002, Sfondrini J Immunol 2006 Effects of protracted sepsis on innate and adaptive immune cells Hotchkiss, Nat Rev Immunol 2013 Conventional adaptive immune response Activation Proliferation Post-septic immune response Anergy Regulatory response T helper- lymphocyte CD28 CTLA-4 TCR PD-1 PD-1 TCR CD40 -L CD40 -L IL-10 IL-12 CD40 CD40 CD86 HLA-DR PDL-1 / PDL-2 PDL-1 / PDL-2 HLA-DR CD86 Antigen-presenting cell Grimaldi, Llitjos & Pène, Med Mal Inf 2014 Infection Steady-state conditions Adapted from Gabrilovich, Nat Rev Immunol 2009 Sepsis-induced expansion of myeloid-derived suppressor cells (MDSC) Delano, J Exp Med 2007 Cancer immune subversion: pivotal role of myeloid cells Dendritic cells - Apoptosis - Loss of IL-12p70 synthesis - Decrease in CMH expression - Induction of Tregs(TGFβ) Macrophages - Decrease in HLA-DR expression - Decrease of CD86 expression - M2 cytokine profile MDSC - Inhibition of T cells - NO and ROS production - L-Arginine depletion Korkar, Cancer Res, 2012 Hotchkiss RS, Moldawer LL. N Engl J Med. 2014 A role of sepsis-induced immune dysfunctions in tumor growth? Polymicrobial sepsis s.c. tumor inoculation Day -14 Day 0 Cavassani, Blood 2010 Nosocomial infections Adapted from Hotchkiss et al., Nat Med 2009 Adapted from Deweerdt, Nat Out 2013 Impact of acute infections on tumor development Tumor cells s.c. ± Plasmodium Chen, PLoS One 2011 Conclusions et perspectives Rôle ambivalent de l’inflammation aiguë sur la croissance tumorale Timing de l’agression par rapport à la phase tumorale Effet transitoire ou prolongé? Mécanismes cellulaires et moléculaires? Pertinence clinique envers le pronostic du cancer
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