Type I IFN protects cancer cells from CD8+ T cell-mediated cytotoxicity after radiation
Type I IFN protects cancer cells from CD8+ T cell-mediated cytotoxicity after radiation
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DOI：
10.1172/jci127458
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发表时间：
2019-10-01
影响因子：
15.9
通讯作者：
Muschel, Ruth J.
中科院分区：
文献类型：
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作者：
Chen, Jianzhou;Cao, Yunhong;Muschel, Ruth J.
用电离辐射治疗肿瘤刺激部分依赖于IFN诱导的抗肿瘤免疫应答。这些IFN直接增强树突状细胞和CD 8（+）T细胞活性。在这里，我们表明，抵抗有效的抗肿瘤免疫反应也是IFN信号在肿瘤的不同细胞区室，癌细胞本身的结果。我们通过基因消除其受体IFNAR 1来消除癌细胞中的I型IFN信号。Ifnar 1基因敲除的4种小鼠癌细胞系的肿瘤在电离辐射后引起明显的免疫应答。这种增强的反应依赖于CD 8（+）T细胞，并通过增强对T细胞介导的杀伤的敏感性来介导。Serpinb 9的诱导被证明是控制辐射后对T细胞杀伤的易感性的潜在机制。Ifnar 1缺陷型肿瘤对有或无放射的抗PD-L1免疫疗法的反应增强。我们的结论是，I型干扰素可以通过调节Serpinb 9保护癌细胞免受T细胞介导的细胞毒性。这一结果有助于解释为什么肿瘤的辐射可以刺激抗肿瘤免疫，但也会导致耐药性。它进一步提出了潜在的干预目标，以改善治疗和预测反应。
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.