Sequential JAK inhibition enhances antitumor immunity after combined anti-PD-1 and anti-CTLA4

While immune checkpoint inhibition (CPI) has reshaped cancer treatment, the majority of patients with cancer do not benefit from this approach, which can also cause immune-related adverse events. Induction of IFN-γ responses is thought be necessary for antitumor immunity, but growing evidence also implicates IFN-γ as a tumor-intrinsic mediator of CPI resistance. CPI-induced IFN-γ mediates activation-induced cell death in T cells as an immune-intrinsic mechanism of resistance. In this study, we found that transient block of IFN-γ signaling through administration of the JAK1 inhibitor ABT-317 enhanced antitumor T cell responses with CPI in preclinical 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 also enhanced memory responses by protecting mice from tumor rechallenge. These results demonstrate that JAK inhibition within a discrete time window following CPI addresses an immune-intrinsic mechanism of therapeutic resistance.