Role of the cGAS-STING pathway in regulating the tumor-immune microenvironment in dMMR/MSI colorectal cancer
Role of the cGAS-STING pathway in regulating the tumor-immune microenvironment in dMMR/MSI colorectal cancer
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DOI：
10.1007/s00262-022-03200-w
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发表时间：
2022-04-16
影响因子：
5.8
通讯作者：
Kono, Koji
中科院分区：
文献类型：
--
作者：
Kaneta, Akinao;Nakajima, Shotaro;Kono, Koji
错配修复缺陷（dMMR）/微卫星不稳定性（MSI）结直肠癌（CRC）具有较高的免疫原性，预后较好。尽管环GMP-AMP合酶（cGAS）-干扰素基因刺激物（STING）途径的激活被认为有助于大量的CD 8（+）TIL，但其在dMMR/MSI CRC中的作用在很大程度上是未知的。在这项研究中，为了检查cGAS-STING途径在dMMR/MSI CRC中募集CD 8（+）TIL的作用，我们使用了我们队列中的公共数据集和临床组织样本来评估pMMR/MSS和dMMR/MSI CRC中cGAS、STING和CD 8（+）TIL的表达。根据公开数据集的分析，cGAS-STING、CD 8效应基因签名和CXCL 10-CCL 5（cGAS-STING通路调控的CD 8（+）TIL的趋化因子）的表达在dMMR/MSI CRC中显著上调，并且cGAS-STING的表达与CD 8效应基因签名的表达显著相关。临床组织样本（n = 283）的免疫组化染色显示，cGAS-STING在dMMR CRC的肿瘤细胞中高表达，肿瘤细胞中cGAS-STING的高表达与CD 8（+）TILs数量的增加显着相关。此外，我们证明了人CRC细胞系中MMR基因的下调增强了cGAS-STING途径的激活。综上所述，我们首次发现dMMR/MSI CRC在肿瘤细胞中保持了高水平的cGAS-STING表达，这可能有助于丰富的CD 8（+）TIL和免疫活性TME。
Deficient mismatch repair (dMMR)/microsatellite instability (MSI) colorectal cancer (CRC) has high immunogenicity and better prognosis compared with proficient MMR (pMMR)/microsatellite stable (MSS) CRC. Although the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been considered to contribute to the high number of CD8(+) TILs, its role in dMMR/MSI CRC is largely unknown. In this study, to examine the role of the cGAS-STING pathway on the recruitment of CD8(+) TILs in dMMR/MSI CRC, we used public datasets and clinical tissue samples in our cohorts to evaluate the expression of cGAS, STING, and CD8(+) TILs in pMMR/MSS and dMMR/MSI CRCs. According to the analysis of public datasets, the expression of cGAS-STING, CD8 effector gene signature, and CXCL10-CCL5, chemoattractants for CD8(+) TILs which regulated by the cGAS-STING pathway, was significantly upregulated in dMMR/MSI CRC, and the expression of cGAS-STING was significantly associated with the expression of CD8 effector gene signature. Immunohistochemistry staining of the clinical tissue samples (n = 283) revealed that cGAS-STING was highly expressed in tumor cells of dMMR CRC, and higher expression of cGAS-STING in tumor cells was significantly associated with the increased number of CD8(+) TILs. Moreover, we demonstrated that the downregulation of MMR gene in human CRC cell lines enhanced the activation of the cGAS-STING pathway. Taken together, for the first time, we found that dMMR/MSI CRC has maintained a high level of cGAS-STING expression in tumor cells, which might contribute to abundant CD8(+) TILs and immune-active TME.