Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer
Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer
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DOI：
10.1158/2159-8290.cd-18-1020
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发表时间：
2019-05-01
期刊：
影响因子：
28.2
通讯作者：
Byers, Lauren A.
中科院分区：
文献类型：
--
作者：
Sen, Triparna;Rodriguez, B. Leticia;Byers, Lauren A.
尽管最近免疫疗法的使用取得了进展，但只有少数小细胞肺癌（SCLC）患者对免疫检查点阻断（ICB）有反应。在这里，我们发现靶向DNA损伤反应（DDR）蛋白PARP和检查点激酶1 （CHK1）可显著增加PD-L1的蛋白和表面表达。PARP或CHK1抑制显著增强PD-L1阻断和细胞毒性t细胞浸润在多种免疫活性SCLC体内模型中的抗肿瘤作用。CD8(+) T细胞耗竭逆转了抗肿瘤作用，证明了CD8(+) T细胞在SCLC中DDR-PD-L1联合阻断中的作用。我们进一步证明，DDR抑制激活了STING/TBK1/IRF3先天免疫途径，导致趋化因子如CXCL10和CCL5水平升高，从而诱导细胞毒性T淋巴细胞的激活和功能。cGAS和STING的敲低成功逆转了DDR和PD-L1联合抑制的抗肿瘤作用。我们的研究结果定义了以前未被识别的先天免疫途径介导的DDR蛋白的免疫调节功能，并为SCLC联合PARP/CHK1抑制剂和免疫疗法提供了理论依据。意义：我们的研究结果明确了DDR抑制剂以前未被认识到的免疫调节功能，并提示在ICB中加入PARP或CHK1抑制剂可能会提高SCLC患者的治疗效果。此外，我们的研究支持先天免疫STING通路在SCLC中ddr介导的抗肿瘤免疫中的作用。参见Hiatt和MacPherson的相关评论，第584页。
Despite recent advances in the use of immunotherapy, only a minority of patients with small cell lung cancer (SCLC) respond to immune checkpoint blockade (ICB). Here, we show that targeting the DNA damage response (DDR) proteins PARP and checkpoint kinase 1 (CHK1) signifi cantly increased protein and surface expression of PD-L1. PARP or CHK1 inhibition remarkably potentiated the antitumor effect of PD-L1 blockade and augmented cytotoxic T-cell infiltration in multiple immunocompetent SCLC in vivo models. CD8(+) T-cell depletion reversed the antitumor effect, demonstrating the role of CD8(+) T cells in combined DDR-PD-L1 blockade in SCLC. We further demonstrate that DDR inhibition activated the STING/TBK1/IRF3 innate immune pathway, leading to increased levels of chemokines such as CXCL10 and CCL5 that induced activation and function of cytotoxic T lymphocytes. Knockdown of cGAS and STING successfully reversed the antitumor effect of combined inhibition of DDR and PD-L1. Our results define previously unrecognized innate immune pathway-mediated immunomodulatory functions of DDR proteins and provide a rationale for combining PARP/CHK1 inhibitors and immunotherapies in SCLC.SIGNIFICANCE: Our results define previously unrecognized immunomodulatory functions of DDR inhibitors and suggest that adding PARP or CHK1 inhibitors to ICB may enhance treatment efficacy in patients with SCLC. Furthermore, our study supports a role of innate immune STING pathway in DDR-mediated antitumor immunity in SCLC.See related commentary by Hiatt and MacPherson, p. 584.