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 CMTM6 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.

中文翻译：

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靶向CMTM6可抑制干细胞样特性并增强头颈部鳞状细胞癌的抗肿瘤免疫力。

CMTM6是PD-L1表达的调节剂，也可以调节肿瘤免疫力。关于CMTM6的功能及其在头颈部鳞状细胞癌（HNSCC）中的作用机理知之甚少。在这项研究中，我们通过IHC分析发现CMTM6过表达预示了HNSCC患者的预后不良。我们发现CMTM6表达与通过Wnt /β-catenin信号传导途径增加的活性相关，这对于肿瘤发生，癌干细胞（CSC）的维持以及多种癌症的上皮间质转化（EMT）至关重要。我们使用短发夹RNA消除了CMTM6的表达，从而导致HNSCC细胞中的核β-连环蛋白表达降低，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，我们在癌症基因组图谱（TCGA）中确定了CMTM6与EMT和CSC相关基因表达之间的显着正相关。我们发现CMTM6的表达与免疫检查点成分之间的RNA和蛋白质均呈正相关。CMTM6沉默诱导的PD-L1下调延迟了SCC7肿瘤的生长，并增加了CD8 +和CD4 + T细胞浸润。在CMTM6敲低组中，PD-1 +，TIM-3 +，VISTA +，LAG-3 +和B7-H3 +耗尽的T细胞的比例显着降低。因此，CMTM6调节干细胞，EMT和T细胞功能障碍，在HNSCC的治疗中可能成为有希望的治疗靶标。我们发现CMTM6的表达与免疫检查点成分之间的RNA和蛋白质均呈正相关。CMTM6沉默诱导的PD-L1下调延迟了SCC7肿瘤的生长，并增加了CD8 +和CD4 + T细胞的浸润。在CMTM6敲低组中，PD-1 +，TIM-3 +，VISTA +，LAG-3 +和B7-H3 +耗尽的T细胞的比例显着降低。因此，CMTM6调节干细胞，EMT和T细胞功能障碍，在HNSCC的治疗中可能成为有希望的治疗靶标。我们发现CMTM6的表达与免疫检查点成分之间的RNA和蛋白质均呈正相关。CMTM6沉默诱导的PD-L1下调延迟了SCC7肿瘤的生长，并增加了CD8 +和CD4 + T细胞的浸润。在CMTM6敲低组中，PD-1 +，TIM-3 +，VISTA +，LAG-3 +和B7-H3 +耗尽的T细胞的比例显着降低。因此，CMTM6调节干细胞，EMT和T细胞功能障碍，在HNSCC的治疗中可能成为有希望的治疗靶标。