Qiang Zhang, Long Jiang, Weiwei Wang, Amanda K Huber, Victoria M Valvo, Kassidy M Jungles, Erin A Holcomb, Ashley N Pearson, Stephanie The, Zhuwen Wang, Leslie A Parsels, Joshua D Parsels, Daniel R Wahl, Arvind Rao, Vaibhav Sahai, Theodore S Lawrence, Michael D Green, Meredith A Morgan
Radiotherapy induces a Type I interferon (T1IFN)-mediated anti-tumoral immune response that we hypothesized could be potentiated by a first-in-class ATM inhibitor leading to enhanced innate immune signaling, T1IFN expression, and sensitization to immunotherapy in pancreatic cancer. We evaluated the effects of AZD1390 or a structurally related compound AZD0156 on innate immune signaling and found that both inhibitors enhanced radiation-induced T1IFN expression via the POLIII/RIG-I/MAVS pathway. In immunocompetent syngeneic mouse models of pancreatic cancer, ATM inhibitor enhanced radiation-induced anti-tumoral immune responses and sensitized to anti-PD-L1, producing immunogenic memory and durable tumor control...
February 20, 2024: JCI Insight