L4.3 No Cure without Immune Responses in Cancer Treated with Cytotoxic Agents

Abstract

We showed that radiotherapy and some chemotherapeutic agents, in particular anthracyclines, oxaliplatine, cyclophosphamide and X Rays can induce anticancer protective CD4+ and CD8+ T cell-based immune responses that result in immunogenic cancer cell death. This anti-cancer immune response then helps to eliminate residual cancer cells (that failed to be killed by chemotherapy) or maintains micrometastases in check, keeping them in a stage of dormancy. We delineated the molecular mechanisms underlying the recognition of dying tumor cells by dendritic cells (DC) and found four major checkpoints that dictate the immunogenicity of cell death. First, optimal phagocytosis of chemotherapy or radiotherapy-treated tumor cells by DC requires the translocation of ER-resident calreticulin (CRT) and disulfide isomerase ERp57 to the plasma membrane of dying tumor cells. Second, the chromatin-binding high mobility group box 1 protein (HMGB1) must be released by dying tumor cells and bind to its receptor toll-like receptor 4 (TLR4) on DC to facilitate antigen processing of the phagocytic cargo (Apetoh et al Nat Med 2007). Third, ATP has to be emitted by dying cells to engage P2RX7 on DC, triggering the activation of a cascade leading to IL-1b-dependent Tc1 polarization of antigen-specific T cell responses. It is important to stress that the antitumor effects of anthracyclines, oxaliplatine and X Rays are abrogated in mice devoid of T cells, of a IFNg/IFNgR functional pathway, of an IL-1b/IL-1R1 intact signaling while IL-12Rb, perforine/TRAIL are dispensable for the tumoricidal effects of these compounds. Fourth, the contexture of the tumor post-chemotherapy revealed that a precise T cell orchestration is required for the immune effectors to reject the tumor burden. Hence, IL-1b-dependent gdT17 cells precede the Tc1 CTL infiltrate and are indispensable for the efficacy of chemotherapy. Immunogenetics will help defining the immunological defects inherent to each individual patients prior to therapy urging for a distinct compensatory treatment while mapping the defects in the CRT exposure pathway may allow to predict tumor intrinsic defects that could be counteracted by defined therapies. Integrating immunological predictors in the current prognosis signatures may lead to personalization of anticancer clinical management.