Zhang and Green et al. demonstrated that pharmacological or genetic inhibition of ATM (a pleiotropic kinase that plays a role in radiation-induced DNA damage response) enhances innate immunity by increasing Type 1 IFN signaling in pancreatic cancer cells in vitro via phosphorylation of the SRC kinase and activation of the TBK1 kinase; this effect was enhanced in combination with radiation. ATM silencing also enhanced intratumoral PD-L1 expression in vivo, and combination with radiation and anti-PD-L1 increased CD8+ TILs, IFNγ, and granzyme B, inhibited tumor growth, and induced immunological memory in mice with pancreatic tumors.
Combinatorial strategies are needed to overcome the resistance of pancreatic cancer to immune checkpoint blockade (ICB). DNA damage activates the innate immune response and improves ICB efficacy. Since ATM is an apical kinase in the radiation-induced DNA damage response, we investigated the effects of ATM inhibition and radiation on pancreatic tumor immunogenicity. ATM was inhibited through pharmacologic and genetic strategies in human and murine pancreatic cancer models both in vitro and in vivo. Tumor immunogenicity was evaluated after ATM inhibition alone and in combination with radiation by assessing TBK1 and Type I Interferon (T1IFN) signaling as well as tumor growth following PD-L1/PD-1 checkpoint inhibition. Inhibition of ATM increased tumoral T1IFN expression in a cGAS/STING-independent, but TBK1 and SRC -dependent manner. The combination of ATM inhibition with radiation further enhanced TBK1 activity, T1IFN production, and antigen presentation. Furthermore, ATM silencing increased PD-L1 expression and increased the sensitivity of pancreatic tumors to PD-L1 blocking antibody in association with increased tumoral CD8+ T cells and established immune memory. In patient pancreatic tumors, low ATM expression inversely correlated with PD-L1 expression. Taken together, these results demonstrate that the efficacy of ICB in pancreatic cancer is enhanced by ATM inhibition and further potentiated by radiation as a function of increased tumoral immunogenicity, underscoring the potential of ATM inhibition in combination with ICB and radiation as an efficacious treatment strategy for pancreatic cancer.