It was for instance shown that TAMs featured the ability to capture anti-PD-1 antibodies, which are thus no longer able to target CD8 T cells (95). showing the ongoing progress in malignancy treatment including ICI and chemotherapy combination strategies. but also induced CD8 T cells Exo1 expressing higher levels of the transcription factor T-bet compared to mice treated with monotherapies. We have investigated the relevance of this observation using mice lacking conditionally the expression of T-bet in CD4 and CD8 T cells. We noted that in these mice the therapeutic effect of Folfox against MC38 colon carcinomas was lost, indicating that T-bet expression in this context was required for the induction of T cell-dependent anticancer immune responses. We also unraveled the signaling pathway driving PD-L1 expression on tumor cells following Folfox administration. Using either T cell-deficient nude mice, mice depleted of CD8 T cells as well as mice receiving IFN neutralizing antibodies, we recognized IFN-secreting CD8 T cells as a major driver of PD-L1 tumor expression following Folfox treatment. While we were unable to rule out a contribution of other IFN-producing cells in our observations, it is notable that we identified a strong correlation between the ability of different chemotherapies to induce CD8 T cell infiltration in the tumor and the induction of Exo1 PD-L1 tumor expression. Overall, Folfox triggers a CD8 T cell-dependent anticancer immune response that in turn drives tumor PD-L1 expression, which thus functions as an adaptive resistance mechanism to the combined therapy. This resistance is usually successfully overcome by the addition of ICI therapy and our results therefore prompt for the combination of immunogenic drugs with ICI (75) (Physique 1). Successful chemo-immunotherapy combinations involving the use of ICI are not restricted to antibodies targeting CTLA-4 or PD-1. Indeed, De Mingo Pulido et al. have just reported in mouse models of breast malignancy that anti-Tim-3 treatment could improve the anticancer effect of paclitaxel (PTX) while anti-PD-1 therapy could not do so (83). Tim-3 was initially characterized as an immunoglobulin expressed on highly polarized Th1 cells (84). We as well as others subsequently showed that Tim-3 was also present on dysfunctional CD8 T cells in mouse and human tumors (17, 18). These findings were relevant as blockade of Tim-3 and PD-L1 could prevent tumor outgrowth (17). Interestingly, while Tim-3 was weakly expressed on CD8 T cells from mouse MMTV-PyMT tumors, the combined therapy induced CD8 T cell anticancer immunity (83). In fact, myeloid cells from both mouse and human tumors expressed Tim-3 and combined therapy with PTX and anti-Tim-3 brought on CXCL9 expression on DCs, possibly enhancing DC/T cell interactions and resulting in anticancer immunity. Accordingly, in human breast cancer patients, CXCL9 expression correlates with response to neoadjuvant chemotherapy (83). Thus, Tim-3 represents a molecular target, which can be exploited in the setting of combinatorial treatments relying on chemotherapy. During ICD certain chemotherapies can also induce the release of various danger signals. For instance, DNA leakage into the cytosol can lead to the engagement of cytosolic DNA sensors, which will trigger the secretion of type I interferon from tumor cells, thereby leading to the induction of anticancer immune responses (74, 85). Chemotherapy also favors the generation of mutations in malignancy cells, thereby increasing their antigenicity and rendering them more sensitive to ICI therapy (54, 86). Some chemotherapies will enhance tumor expression of MHC molecules, which enhances their ability to present tumor antigens and thus immunogenicity (85, 87, 88). Drugs like CTX can also drive lymphopenia, which can be exploited therapeutically in the context of combination therapies to drive immune activation and anticancer immunity (89C92). Thus, chemotherapy can be an attractive partner of ICI that can overcome ICI resistance due to insufficient anti-tumor Exo1 T cell generation. Chemotherapy Resets the TME to Favor T-cell Effector Function Immunosuppressive cells present in the TME compromise the anticancer efficacy of ICI. Mouse studies have documented that myeloid cells, including tumor-associated macrophages (TAMs) and MDSCs, as well as Tregs and Th2 lymphocytes can contribute to the repression of anticancer T cell responses following ICI administration (27, 43, 45). Mouse Monoclonal to KT3 tag Accordingly, preventing the accumulation of these immunosuppressive.