Abstract CN2-1: Personalized chemotherapy of cancer based on immune parameters

Abstract

Abstract Recent data suggest that therapy-induced immunogenic cancer cell death can stimulate a therapeutic anti-cancer immune response that then contributes to the control (or even to the elimination) of residual tumor cells. Indeed, some chemotherapeutic agents (e.g. X Rays, oxaliplatin and anthracyclines) can induce immunogenic apoptosis, while others cannot (e.g. cisplatin, mitomycin C and etoposide) [Casares, 2005; Obeid, 2007; Apetoh, 2007; Obeid, 2007; Ghiringhelli, 2009]. Thus far, we know that the immunogenicity of tumor cell death is closely linked to the surface exposure of calreticuline (CRT), the secretion of ATP and the release of HMGB1 that bind to CRT receptor, P2RX7 and TLR4 on host dendritic cells respectively. Chemotherapeutic agents that fail to induce CRT exposure or HMGB1 release are unable to induce immunogenic cell death. Our published data indicate that two loss-of-function alleles (that affect toll-like receptor-4 [TLR4] and purinergic P2 receptor X7 [P2RX7] of 12 and 30% of Caucasians, respectively) reduce the efficacy of conventional anticancer therapies, for instance in anthracyline-treated breast carcinomas and in oxaliplatin-treated colon cancers. We have determined novel defects in the emission or perception of immunogenic cell death signals negatively affecting the therapeutic response of human cancers that will be presented. Mouse preclinical models allowed us to unravel novel cellular and molecular pathways involved in the immunogenicity of cell death. These data will be reviewed. Based on this concept, which remains to be proven, one can formulate four predictions: First, therapeutic regimens that are intrinsically unable to elicit immunogenic death should be less efficient than therapies that can trigger immunogenic cell death. Second, cancers that intrinsically lack the capacity to emit immunogenic signals during tumor cell death should fail to induce a specific immune response and have a bad prognosis. Third, immune defects that weaken the response against dying tumor cells, including defects in the perception of immunogenic signals, should worsen the prognosis of cancer and compromise the therapeutic response. Fourth, the immunogenic cell death induced by chemotherapy should influence the composition and the architecture of the immune infiltrate present in tumors, which in turn should affect the therapeutic response. Citation Information: Clin Cancer Res 2010;16(7 Suppl):CN2-1