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 September 4, 2019
Citation Information: J Clin Invest. 2019;129(10):4224-4238. https://doi.org/10.1172/JCI127458.
View: Text | PDF
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

×

Figure 2

The enhanced response of Ifnar1-KO tumors to IR is mediated by CD8+ T cell immunity.

Options: View larger image (or click on image) Download as PowerPoint
The enhanced response of Ifnar1-KO tumors to IR is mediated by CD8+ T ce...
MC38 tumors (WT and Ifnar1-KO) grown in CD-1 nude mice were treated with 0 Gy (n = 7–8) or 10 Gy (n = 13–14) IR. (A and B) Tumor volumes and mouse survival were assessed and summarized. C57BL/6 mice bearing subcutaneous WT (C) or Ifnar1-KO (D) MC38 tumors were subjected to the following treatments: 0 Gy IR; 10 Gy IR on day 0 plus isotype control Abs (10 Gy + iso); 10 Gy IR plus anti-CD8α Ab; and 10 Gy IR plus anti-NK1.1 Ab. Abs were administered on days –1, 2, 5, 8, and 11. n = 8–10. WT (C) or Ifnar1-KO (D) tumors with either CD8+ T cells or NK cells depleted were compared with tumors receiving isotype control Abs. (E) Growth of WT and Ifnar1-KO MC38 tumors following 10 Gy IR with CD8+ T cell depletion. (F) Mean volume of tumors on day 8 after IR was compared in WT and Ifnar1-KO mice. C57BL/6 mice with completely regressed Ifnar1-KO MC38 tumors after IR were rechallenged with WT or Ifnar1-KO MC38 cell on the other flank. (G) Growth of tumors following reinoculation. n = 4–6. Data show mean ± SEM (A–E and G) and mean ± SD (F). Comparison of 2 means was performed by the unpaired Student’s t test when data were normally distributed, and the Mann-Whitney U test when they were not or their normality could not be evaluated. Comparison of means of more than 2 groups was performed by 1-way ANOVA with Tukey’s multiple-comparisons test (NS: P ≥ 0.05, *P < 0.05, **P < 0.01, ***P < 0.001).