The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
Cancer Immunol Res. 2020 Feb;8(2):179-191. doi: 10.1158/2326-6066.CIR-19-0394. Epub 2019 Nov 26.
CMTM6, a regulator of PD-L1 expression, also modulates tumor immunity. Little is known about the function of CMTM6 and its mechanism of action in head and neck squamous cell carcinoma (HNSCC). In this study, we found by IHC analysis that CMTM6 overexpression predicted a poor prognosis for patients with HNSCC. We discovered that CMTM6 expression was correlated with increased activity through the Wnt/β-catenin signaling pathway, which is essential for tumorigenesis, maintenance of cancer stem cells (CSC), and the epithelial-to-mesenchymal transition (EMT) characteristic of multiple cancers. We used short hairpin RNA to eliminate expression of CMTM6, which led, in HNSCC cells, to reduced expression of nuclear β-catenin as well as inhibition of stem cell-like properties, TGFβ-induced EMT, and cell proliferation. Consistent with these results, we identified a significant positive correlation between expression of and EMT- and CSC-related genes in The Cancer Genome Atlas (TCGA). We found positive correlations for both RNA and protein between expression of CMTM6 and immune checkpoint components. CMTM6 silencing-induced PD-L1 downregulation delayed SCC7 tumor growth and increased CD8 and CD4 T-cell infiltration. The proportions of PD-1, TIM-3, VISTA, LAG-3, and B7-H3 exhausted T cells were decreased significantly in the CMTM6 knockdown group. CMTM6 thus regulates stemness, EMT, and T-cell dysfunction and may be a promising therapeutic target in the treatment of HNSCC.
CMTM6 是 PD-L1 表达的调节剂，也能调节肿瘤免疫。目前对 CMTM6 的功能及其在头颈部鳞状细胞癌（HNSCC）中的作用机制知之甚少。在这项研究中，我们通过免疫组化分析发现，CMTM6 过表达预示着 HNSCC 患者预后不良。我们发现，CMTM6 的表达与 Wnt/β-catenin 信号通路的活性增加相关，该通路对肿瘤发生、癌症干细胞（CSC）的维持以及多种癌症的上皮-间充质转化（EMT）特征至关重要。我们使用短发夹 RNA 消除 CMTM6 的表达，这导致 HNSCC 细胞中核 β-catenin 的表达减少，并抑制了干细胞样特性、TGFβ 诱导的 EMT 和细胞增殖。与这些结果一致的是，我们在癌症基因组图谱（TCGA）中发现了 和 EMT 和 CSC 相关基因之间存在显著的正相关。我们发现 CMTM6 的表达与免疫检查点成分的 RNA 和蛋白质之间存在正相关。CMTM6 沉默诱导的 PD-L1 下调延迟 SCC7 肿瘤生长并增加 CD8 和 CD4 T 细胞浸润。CMTM6 敲低组中 PD-1、TIM-3、VISTA、LAG-3 和 B7-H3 耗尽 T 细胞的比例显著降低。因此，CMTM6 调节干性、EMT 和 T 细胞功能障碍，可能是治疗 HNSCC 的有前途的治疗靶点。
