State Key Laboratory of Oncology in South China & Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
J Immunother Cancer. 2021 Feb;9(2). doi: 10.1136/jitc-2020-001638.
BACKGROUND: CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6), a programmed death-ligand 1 (PD-L1) regulator, is widely expressed in various tumors and regulates the immune microenvironment. However, its prognostic value remains controversial, and the roles of CMTM6 in colorectal cancer (CRC) are still unknown. In this study, we aimed to elaborate the expression patterns of CMTM6 and PD-L1 in CRC and investigate their relationship with the infiltration of T cells and the prognosis of patients with CRC. METHODS: Analysis of CMTM6 mRNA levels, gene ontology enrichment analysis and single-sample gene set enrichment analysis were performed in a The Cancer Genome Atlas colon cancer cohort. The expression of CMTM6 and PD-L1 and the infiltration of T cells in tumor tissues from our cohort containing 156 patients with CRC receiving adjuvant chemotherapy and 77 patients with CRC without chemotherapy were examined by immunohistochemistry assay. RESULTS: CMTM6 expression was upregulated in CRC compared with normal colon tissues, and CMTM6 levels were lower in advanced tumors than in early-stage tumors. High expression of CMTM6 correlated with lower pT stage and more CD4/CD8 tumor-infiltrating lymphocytes (TILs) and predicted a favorable prognosis in CRC. PD-L1 was expressed in CRC tissues at a low level, and PD-L1 positivity in tumor stroma (PD-L1(TS)), but not PD-L1 positivity in cancer cells (PD-L1(CC)), was associated with an increased density of CD4 TILs and a favorable prognosis. The coexpression status of CMTM6 and PD-L1(TS) divided patients with CRC into three groups with low, moderate and high risks of progression and death, and patients with CMTM6/PD-L1(TS) status had the longest survival. Moreover, the prognostic value of CMTM6/PD-L1 expression was more significant in patients with CRC treated with adjuvant chemotherapy than in those not treated with chemotherapy. CONCLUSION: CMTM6 has a critical impact on the immune microenvironment and can be used as an independent prognostic factor for CRC. The coexpression status of CMTM6 and PD-L1 can be used as a new classification to stratify the risk of progression and death for patients with CRC, especially for patients receiving adjuvant chemotherapy. These findings may provide insights into improving responses to immunotherapy-included comprehensive treatment for CRC in the future.
背景：CKLF 样 MARVEL 跨膜结构域包含 6 型（CMTM6）是程序性死亡配体 1（PD-L1）的调节因子，广泛表达于各种肿瘤中，调节免疫微环境。然而，其预后价值仍存在争议，CMTM6 在结直肠癌（CRC）中的作用尚不清楚。在本研究中，我们旨在阐述 CRC 中 CMTM6 和 PD-L1 的表达模式，并研究其与 T 细胞浸润及 CRC 患者预后的关系。
方法：在癌症基因组图谱结肠癌队列中进行 CMTM6 mRNA 水平分析、基因本体富集分析和单样本基因集富集分析。采用免疫组织化学法检测我们的队列中 156 例接受辅助化疗的 CRC 患者和 77 例无化疗的 CRC 患者肿瘤组织中 CMTM6 和 PD-L1 的表达及 T 细胞浸润。
结果：与正常结肠组织相比，CRC 中 CMTM6 表达上调，且晚期肿瘤中 CMTM6 水平低于早期肿瘤。CMTM6 高表达与较低的 pT 分期、更多的 CD4/CD8 肿瘤浸润淋巴细胞（TILs）相关，并预测 CRC 预后良好。CRC 组织中 PD-L1 低表达，肿瘤基质中 PD-L1 阳性（PD-L1(TS)），而肿瘤细胞中 PD-L1 阳性（PD-L1(CC)）与 CD4 TILs 密度增加和预后改善相关。CMTM6 和 PD-L1(TS) 的共表达状态将 CRC 患者分为低、中、高进展和死亡风险组，CMTM6/PD-L1(TS) 状态患者的生存时间最长。此外，CMTM6/PD-L1 表达的预后价值在接受辅助化疗的 CRC 患者中比未接受化疗的患者更显著。
结论：CMTM6 对免疫微环境有重要影响，可作为 CRC 的独立预后因素。CMTM6 和 PD-L1 的共表达状态可作为新的分类方法，对 CRC 患者的进展和死亡风险进行分层，特别是对接受辅助化疗的患者。这些发现可能为改善包括免疫治疗在内的综合治疗 CRC 的反应提供思路。
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