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

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.

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Fig. 1: Tumor cells hijack intrinsic apoptosis to restrict type I IFN production after radiation.
Fig. 2: Tumor-intrinsic CASP9 signaling suppresses radiation-induced antitumor immunity.
Fig. 3: Blocking CASP9 signaling to facilitate tumor-intrinsic mtDNA sensing after radiation.
Fig. 4: Casp9−/− tumor-derived dsDNA innate sensing is required for provoking radiation-mediated antitumor immunity.
Fig. 5: Tumors evolve resistance to adaptive immunity by upregulating PD-L1.
Fig. 6: Emricasan synergizes with radiation and anti-PD-L1.

Data availability

All data supporting the findings of this study are available within the article and its supplementary information files and from the corresponding author upon reasonable request. A reporting summary for this article is available as a Supplementary Information file.

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Acknowledgements

We thank R. W. Welchselbaum for providing reagents and assisting with experiments and the UT southwestern Flow Cytometry Facility and Animal Resources Center. YXF holds the Mary Nell and Ralph B. Rogers Professorship in Immunology. This work was supported by NCI CA134563, Texas CPRIT grant RR150072 and RR180725 (established CPRIT scholar in cancer research) to Y.-X. F.

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Contributions

C.H., Z.L. and Y.-X.F. designed experiments and analyzed data. C.H. and Z.L. performed experiments. C.H. and Y.-X.F. wrote the manuscript. Z.L. J.Q. and C.M. revised the manuscript. Y.Z. and C.-L.Z. helped with SIM imaging. A.S., C.D., A.Z., Z.R., C.L. and X.C. provided mice and reagents. J.Q. gave valuable advice. Y.-X.F. supervised the project.

Corresponding authors

Correspondence to Jian Qiao or Yang-Xin Fu.

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Editor recognition statement: Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Han, C., Liu, Z., Zhang, Y. et al. Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling. Nat Immunol 21, 546–554 (2020). https://doi.org/10.1038/s41590-020-0641-5

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