Nakajima Shotaro, Kaneta Akinao, Okayama Hirokazu, Saito Katsuharu, Kikuchi Tomohiro, Endo Eisei, Matsumoto Takuro, Fukai Satoshi, Sakuma Mei, Sato Takahiro, Mimura Kosaku, Saito Motonobu, Saze Zenichiro, Sakamoto Wataru, Onozawa Hisashi, Momma Tomoyuki, Kono Koji
Department of Multidisciplinary Treatment of Cancer and Regional Medical Support, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
Cancers (Basel). 2023 May 18;15(10):2826. doi: 10.3390/cancers15102826.
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in activating immune cells in the tumor microenvironment, thereby contributing to a more favorable response to immune checkpoint inhibitors (ICI) in colorectal cancer (CRC). However, the impact of the expression of cGAS-STING in tumor cells on the infiltration of CD8 T cells and clinical outcomes in mismatch repair proficient/microsatellite stable (pMMR/MSS) CRC remains largely unknown. Our findings reveal that 56.8% of all pMMR CRC cases were cGAS-negative/STING-negative expressions (cGAS/STING) in tumor cells, whereas only 9.9% of all pMMR CRC showed cGAS-positive/STING-positive expression (cGAS/STING) in tumor cells. The frequency of cGAS/STING cases was reduced in the advanced stages of pMMR/MSS CRC, and histone methylation might be involved in the down-regulation of STING expression in tumor cells. Since the expression level of cGAS-STING in tumor cells has been associated with the infiltration of CD8 and/or CD4 T cells and the frequency of recurrence in pMMR/MSS CRC, decreased expression of cGAS-STING in tumor cells might lead to poor immune cell infiltration and worse prognosis in most pMMR/MSS CRC patients. Our current findings provide a novel insight for the treatment of patients with pMMR/MSS CRC.
环磷酸鸟苷-腺苷合成酶（cGAS）-干扰素基因刺激因子（STING）通路在激活肿瘤微环境中的免疫细胞方面起着关键作用，从而有助于结直肠癌（CRC）对免疫检查点抑制剂（ICI）产生更有利的反应。然而，肿瘤细胞中cGAS-STING的表达对错配修复 proficient/微卫星稳定（pMMR/MSS）CRC中CD8 T细胞浸润和临床结局的影响仍 largely未知。我们的研究结果显示，所有pMMR CRC病例中56.8%的肿瘤细胞为cGAS阴性/STING阴性表达（cGAS/STING），而所有pMMR CRC中只有9.9%的肿瘤细胞显示cGAS阳性/STING阳性表达（cGAS/STING）。在pMMR/MSS CRC的晚期阶段，cGAS/STING病例的频率降低，并且组蛋白甲基化可能参与肿瘤细胞中STING表达的下调。由于肿瘤细胞中cGAS-STING的表达水平与pMMR/MSS CRC中CD8和/或CD4 T细胞的浸润以及复发频率相关，肿瘤细胞中cGAS-STING表达的降低可能导致大多数pMMR/MSS CRC患者免疫细胞浸润不良和预后较差。我们目前的研究结果为pMMR/MSS CRC患者的治疗提供了新的见解。
