Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling

Chuanhui Han, Zhida Liu, Yunjia Zhang, Aijun Shen, Chunbo Dong, Anli Zhang, Casey Moore, Zhenhua Ren, Changzheng Lu, Xuezhi Cao, Chun Li Zhang, Jian Qiao, Yang-Xin Fu

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9−/− tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.

Original languageEnglish (US)
Pages (from-to)546-554
Number of pages9
JournalNature immunology
Volume21
Issue number5
DOIs
StatePublished - May 1 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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