IL-15 AGONISTS OVERCOME THE IMMUNOSUPPRESSIVE EFFECTS OF MEK INHIBITORS

Many signal transduction inhibitors being developed for cancer therapy target pathways that are also important for the proper function of anti-tumor lymphocytes, possibly weakening their therapeutic effects. Here we show that most inhibitors targeting multiple signaling pathways have especially strong negative effects on T cell activation at their active doses on cancer cells. In particular, we found that recently approved MEK inhibitors displayed potent suppressive effects on T cells in vitro. However, these effects could be attenuated by certain cytokines that can be administered to cancer patients. Among them, clinically available IL-15 superagonists, which can activate PI3K selectively in T lymphocytes, synergized with MEK inhibitors in vivo to elicit potent and durable antitumor responses, including by a vaccine-like effect that generated resistance to tumor re-challenge. Our work identifies a clinically actionable approach to overcome the T cell-suppressive effects of MEK inhibitors, and illustrates how to reconcile the deficiencies of signal transduction inhibitors which impede desired immunological effects in vivo.