Quantitative analysis of CMTM6 expression in tumor microenvironment in metastatic melanoma and association with outcome on immunotherapy.
Quantitative analysis of CMTM6 expression in tumor microenvironment in metastatic melanoma and association with outcome on immunotherapy.
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DOI：
10.1080/2162402x.2020.1864909
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发表时间：
2020-12-29
期刊：
影响因子：
7.2
通讯作者：
Rimm DL
中科院分区：
文献类型：
--
作者：
Martinez-Morilla S;Zugazagoitia J;Wong PF;Kluger HM;Rimm DL
趋化因子样因子（CKLF）样MARVEL跨膜结构域6 （CMTM6）通过保护程序性死亡配体-1 （PD-L1）免受泛素介导的降解而调节许多蛋白质的降解，包括PD-L1。在这个作用下，它可以调节免疫治疗的有效性。在这里，我们首次表征了CMTM6在黑色素瘤中的表达，并评估了其与免疫检查点抑制剂（ICI）反应的关系。我们在组织微阵列（TMA）中使用定量免疫荧光（QIF）评估了60例接受免疫治疗的转移性黑色素瘤患者的预处理活检组织中CMTM6、PD-L1和其他免疫相关蛋白的表达。对照患者的mRNA表达也从癌症基因组图谱（TCGA）数据库中获得。CMTM6的表达与PD-L1、CD3、CD20和CD68标志物在蛋白（Pearson’s r = 0.53-0.81，均P < 0.0001）和mRNA （Spearman’s r = 0.15-0.44，均P < 0.002，除CD68外，P = 0.26）水平上呈正相关。在基质和所有免疫区（T细胞、B细胞和巨噬细胞）中测量CMTM6蛋白与免疫治疗后更长的生存期相关（P = .007）。多变量分析还显示，在间质室（风险比(HR) = 0.12, P = 0.001）和cd68阳性（HR = 0.30, P = 0.043）中测量CMTM6生存率时存在显著关联。此外，PD-L1而非CMTM6在对照患者中显示预后价值。最后，间质室中CMTM6和PD-L1的高共表达与治疗患者的更长的生存期显著相关（P = 0.028）。因此，CMTM6表达显示出作为ICI治疗预测因素的潜力。
Chemokine-like factor (CKLF)-like MARVEL transmembrane domain containing 6 (CMTM6) modulates degradation of a number of proteins, including programmed death ligand-1 (PD-L1) by protecting it from ubiquitin-mediated degradation. In this role, it could modulate the effectiveness of immunotherapy. Here, for the first time, we characterize CMTM6 expression in melanoma and evaluate its association with response to immune checkpoint inhibitors (ICI). We evaluated the expression of CMTM6, PD-L1 and other immune-related proteins in 60 pretreatment biopsies from metastatic melanoma patients who received immunotherapy, in a tissue microarray (TMA) using quantitative immunofluorescence (QIF). Expression of mRNA from control patients obtained from The Cancer Genome Atlas (TCGA) database was also compared. CMTM6 expression was positively correlated with PD-L1, CD3, CD20, and CD68 markers, at protein (Pearson’s r = 0.53–0.81, all P < .0001) and mRNA (Spearman’s r = 0.15–0.44, all P < .002, except for CD68 where P = .26) levels. CMTM6 protein was associated with longer survival after immunotherapy when measured in the stromal (P = .007) and all the immune compartments tested (T cells, B cells, and macrophages). Multivariable analyses also revealed significant CMTM6 survival associations when measured in stromal (Hazard Ratio (HR) = 0.12, P = .001) and CD68-positive (HR = 0.30, P = .043) compartments. Additionally, PD-L1 but not CMTM6 showed prognostic value in control patients. Finally, high CMTM6 and PD-L1 co-expression in the stromal compartment was significantly associated with longer survival in treated patients (P = .028). Consequently, CMTM6 expression shows potential as a predictive factor for ICI treatments.