DNA-PK Inhibition and Radiation Promote Antitumoral Immunity through RNA Polymerase III in Pancreatic Cancer.

Abstract

Targeting the DNA damage response in combination with radiation enhances type I interferon (T1IFN)-driven innate immune signaling. It is not understood, however, whether DNA-dependent protein kinase (DNA-PK), the kinase critical for repairing the majority of radiation-induced DNA double-strand breaks in cancer cells, is immunomodulatory. We show that combining radiation with DNA-PK inhibition increases cytosolic double-stranded DNA and tumoral T1IFN signaling in a cyclic GMP-AMP synthase (cGAS)- and stimulator of interferon genes (STING)-independent, but an RNA polymerase III (POL III), retinoic acid-inducible gene I (RIG-I), and antiviral-signaling protein (MAVS)-dependent manner. Although DNA-PK inhibition and radiation also promote programmed death-ligand 1 (PD-L1) expression, the use of anti-PD-L1 in combination with radiation and DNA-PK inhibitor potentiates antitumor immunity in pancreatic cancer models. Our findings demonstrate a novel mechanism for the antitumoral immune effects of DNA-PK inhibitor and radiation that leads to increased sensitivity to anti-PD-L1 in poorly immunogenic pancreatic cancers.

IMPLICATIONS:

Our work nominates a novel therapeutic strategy as well as its cellular mechanisms pertinent for future clinical trials combining M3814, radiation, and anti-PD-L1 antibody in patients with pancreatic cancer.

• Authors: Weiwei Wang, Matthew T McMillan, Xinyi Zhao, Zhuwen Wang, Long Jiang, David Karnak, Fatima Lima, Joshua D Parsels, Leslie A Parsels, Theodore S Lawrence, Timothy L Frankel, Meredith A Morgan, Michael D Green, Qiang Zhang
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 20 Issue 7 Pg. 1137-1150 (07 06 2022) ISSN: 1557-3125 [Electronic] United States
• PMID: 35348737 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Protein Kinase Inhibitors
• Pyridazines
• Quinazolines
• Protein Kinases
• DNA-Activated Protein Kinase
• RNA Polymerase III
• peposertib

Topics

• DNA-Activated Protein Kinase (antagonists & inhibitors)
• Humans
• Pancreatic Neoplasms (drug therapy, immunology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Kinases
• Pyridazines
• Quinazolines
• RNA Polymerase III