Inhibition of ATM Increases Interferon Signaling and Sensitizes Pancreatic Cancer to Immune Checkpoint Blockade Therapy.

Abstract

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. Because 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. SIGNIFICANCE: This study demonstrates that ATM inhibition induces a T1IFN-mediated innate immune response in pancreatic cancer that is further enhanced by radiation and leads to increased sensitivity to anti-PD-L1 therapy.See related commentary by Gutiontov and Weichselbaum, p. 3815.

• Authors: Qiang Zhang, Michael D Green, Xueting Lang, Jenny Lazarus, Joshua D Parsels, Shuang Wei, Leslie A Parsels, Jiaqi Shi, Nithya Ramnath, Daniel R Wahl, Marina Pasca di Magliano, Timothy L Frankel, Ilona Kryczek, Yu L Lei, Theodore S Lawrence, Weiping Zou, Meredith A Morgan
• Journal: Cancer research (Cancer Res) Vol. 79 Issue 15 Pg. 3940-3951 (Aug 01 2019) ISSN: 1538-7445 [Electronic] United States
• PMID: 31101760 (Publication Type: Journal Article)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Interferons
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins

Topics

• Animals
• Ataxia Telangiectasia Mutated Proteins
• CD8-Positive T-Lymphocytes
• Humans
• Immunotherapy
• Interferons
• Mice
• Pancreatic Neoplasms
• Signal Transduction