Sequential JAK inhibition boosts antitumor T cell responses to combined anti-PD-1 and anti-CTLA4

While immune Checkpoint Inhibition (CPI) has reshaped cancer treatment, the majority of cancer patients do not benefit from this treatment approach, and this treatment can lead to immune related adverse events. While induction of IFNγ responses are thought be necessary for anti-tumor immunity, growing evidence also implicates IFNγ as a tumor-intrinsic mediator of CPI resistance. CPI-induced IFNγ also mediates activation induced cell death in T cells as an immune-intrinsic mechanism of resistance. In this study, we show that transient block of IFNγ signaling through administration of the JAK1 inhibitor ABT-317 enhances anti-tumor T cell responses with CPI in pre-clinical models. Importantly sequential but not concomitant ABT-317 treatment, led to significantly reduced toxicity and improved tumor efficacy. Sequential treatment reduced activation-induced T cell death and enhanced expansion of tumor-reactive T cell subsets with increased effector function in vivo and ex vivo. Only CPI in combination with ABT-317 was able to protect mice from tumor rechallenge. These results demonstrate that the JAK inhibition within a window following CPI can used to address an immune-intrinsic mechanism of therapeutic resistance.