RFAT

Primary tumors are currently treated by a combination of therapies including, in most cases, surgery, local radiotherapy, and adjuvant chemotherapy. Even when the tumor has apparently been defeated, micrometastases of dormant tumor cells frequently lead to tumor relapse and final therapeutic failure. Accumulating evidence indicates that the innate and adaptive immune systems can make a crucial contribution to the antitumor effects of conventional chemotherapy-based cancer treatments. However, the tumor-mediated immunosuppression of the host often limits the initiation of an effective anticancer immune response. Therefore, to defeat cancer, it is essential to relieve host immunosuppression to unleash an immune response that eradicates residual tumor cells. We have identified that 5-Fluorouracil (5-FU), a pyrimidine analog that is mainly used in the treatment of breast and colon cancer, has a superior and selective ability to deplete Myeloid derived suppressor cells (MDSC) in vivo. The elimination of MDSC by 5-FU partly restored anticancer responses and improved 5-FU therapeutic effect. However, our preliminary data indicate that an additional molecular pathway activated by the 5-FU-mediated cell death of MDSC limits the efficacy of 5-FU and contributes to immune evasion. Specifically, we hypothesize that 5-FU triggers an inflammatory, caspase-1-dependent cell death of MDSC, which supports the IL-1ß-mediated polarization of intratumor Th17 cells that impair the development of anticancer responses. Thus, by identifying the molecular mechanisms by which 5-FU affects MDSC, this project ultimately aims at unraveling new molecular targets that could be modulated to achieve optimal anticancer responses.