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Type I IFN protects cancer cells from CD8+ T cell–mediated cytotoxicity after radiation
Jianzhou Chen, … , Jenny A.F. Vermeer, Ruth J. Muschel
Jianzhou Chen, … , Jenny A.F. Vermeer, Ruth J. Muschel
Published October 1, 2019; First published September 4, 2019
Citation Information: J Clin Invest. 2019;129(10):4224-4238. https://doi.org/10.1172/JCI127458.
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Categories: Research Article Immunology Oncology

Type I IFN protects cancer cells from CD8+ T cell–mediated cytotoxicity after radiation

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Abstract

Treatment of tumors with ionizing radiation stimulates an antitumor immune response partly dependent on induction of IFNs. These IFNs directly enhance dendritic cell and CD8+ T cell activity. Here we show that resistance to an effective antitumor immune response is also a result of IFN signaling in a different cellular compartment of the tumor, the cancer cells themselves. We abolished type I IFN signaling in cancer cells by genetic elimination of its receptor, IFNAR1. Pronounced immune responses were provoked after ionizing radiation of tumors from 4 mouse cancer cell lines with Ifnar1 knockout. This enhanced response depended on CD8+ T cells and was mediated by enhanced susceptibility to T cell–mediated killing. Induction of Serpinb9 proved to be the mechanism underlying control of susceptibility to T cell killing after radiation. Ifnar1-deficient tumors had an augmented response to anti–PD-L1 immunotherapy with or without radiation. We conclude that type I IFN can protect cancer cells from T cell–mediated cytotoxicity through regulation of Serpinb9. This result helps explain why radiation of tumors can stimulate antitumor immunity yet also result in resistance. It further suggests potential targets for intervention to improve therapy and to predict responses.

Authors

Jianzhou Chen, Yunhong Cao, Bostjan Markelc, Jakob Kaeppler, Jenny A.F. Vermeer, Ruth J. Muschel

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Figure 1

Ifnar1 KO in cancer cells enhances tumor response to IR.

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Ifnar1 KO in cancer cells enhances tumor response to IR.
Tumors in C57B...
Tumors in C57BL/6 mice derived from the indicated cancer cell lines with or without Ifnar1 KO, including MC38 (A and B), B16F10 (C and D), KPC (E and F), and LLC (G and H) cells, received 0 Gy or the indicated single doses of IR. (A, C, E, and G) Tumor volume. Note that once mice had been culled due to reaching the ethically acceptable limit for tumor volume, the tumors from those mice no longer were included in the mean tumor volume calculation. (B, D, F, and H) Kaplan-Meier survival curves from the same experiment. n = 7–18 in control groups and 8–20 in irradiation groups. Error bars represent mean ± SEM. Comparison of 2 means was performed by the Mann-Whitney U test. Survival comparison between groups were performed using log-rank test (NS: P ≥ 0.05, *P < 0.05, **P < 0.01, ***P < 0.001).
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Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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