Type I IFN protects cancer cells from CD8+ T cell–mediated cytotoxicity after radiation
Jianzhou Chen, Yunhong Cao, Bostjan Markelc, Jakob Kaeppler, Jenny A.F. Vermeer, Ruth J. Muschel
Jianzhou Chen, Yunhong Cao, Bostjan Markelc, Jakob Kaeppler, Jenny A.F. Vermeer, Ruth J. Muschel
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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 7

Overexpression of Serpinb9 in Ifnar1-KO cancer cells reduces enhanced killing by CD8+ T cells in vitro.

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Overexpression of Serpinb9 in Ifnar1-KO cancer cells reduces enhanced ki...
WT and Ifnar1-KO MC38 cells were cocultured with CD8+ T cells isolated from WT MC38 tumors for 48 hours with or without Z-AAD-CMK. CD8+ T cells were treated with Z-AAD-CMK (100 μM) for 30 minutes prior to coculture. Z-AAD-CMK remained in the medium through the experiment. (A) Percentage of cell killing. n = 4. MC38 cells (WT, Ifnar1-KO + vector, and Ifnar1-KO + Serpinb9 overexpression [SB9 OE]) were cocultured with CD8+ T cells isolated from WT MC38 tumors. (B) Percentage of cell killing. n = 4. MC38 cells (WT, Ifnar1-KO + vector, and Ifnar1-KO + SB9 OE) were cocultured with either control medium or CD8+ T cells isolated from WT MC38 tumors for 4 hours with propidium iodide (50 μg/mL) in the medium. (C) Percentage of propidium iodide–positive cells following coculture. n = 4. Data represent mean ± SD. Comparison of means 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).