Postdoctoral researcher UCSF San Francisco, California, United States
Immune checkpoint blockade (ICB) represents an established treatment for many cancers. However, most patients treated with ICB ultimately show disease progression. We have previously demonstrated that combining anti-PD1 and anti-CTLA-4 can induce activation-induced cell death of tumor reactive T cells leading to compromised anti-tumor efficacy and immunologic memory. We have also shown that this selective deletion of T cells is mediated by interferon g (IFNg). Since IFNg is also pivotal for the mediating antitumor responses, we investigated approaches to rescue tumor reactive T cells without compromising tumor efficacy. Because IFNGR1 signals through Jak1, we examined whether a JAK inhibitor (JAKi) could be used to enhance the effectiveness of combination of anti-PD-1 and anti-CTLA4. We found that administrating JAKi in a specific sequence leads to significantly increased rates of tumor rejection and survival. We also observed that T cell activation is maintained and even increased with time in the mice treated with JAKi. Importantly, tumor-reactive T cells are effectively expanded in the tumor-draining lymph nodes of those mice, potentially contributing to the observed antitumor efficacy. We also observed partial depletion of regulatory T cells in responding mice, indicating that activation induced cell death (AICD) is reduced in the presence of JAKi. Our results demonstrate that temporal modulation of IFNg can enhance anti-tumor immune responses leading to improved outcomes.
