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

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 9

Ifnar1-KO or Serpinb9-KO tumors exhibited greater levels of response to anti–PD-L1 with or without IR than WT tumors.

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Ifnar1-KO or Serpinb9-KO tumors exhibited greater levels of response to...
C57BL/6 mice bearing subcutaneous WT or Ifnar1-KO MC38 tumors were subjected to the following treatments: isotype control Ab; anti–PD-L1 Ab; 10 Gy IR on day 0 plus isotype control Ab; 10 Gy IR plus anti–PD-L1 Ab. Ab was administrated on days –1, 3, 7, and 11. (A, C, and E) Tumor volumes. (B, D, and F) Kaplan-Meier survival curves for mice. n = 5–7. C57BL/6 mice bearing subcutaneous WT, Ifnar1-KO, or SB9 KO B16F10 tumors received anti–PD-L1 Ab on days –1, 3, 7, and 11 with or without 20 Gy IR on day 0. (G–J) Tumor growth and survival. n = 5–8. Data represent mean ± SEM. Comparison of 2 means was performed with the Mann-Whitney U test. Survival comparisons between groups were performed using the log-rank test (NS: P ≥ 0.05, *P < 0.05, **P < 0.01, ***P < 0.001).