Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
J Cancer Res Clin Oncol. 2021 Jul;147(7):2003-2011. doi: 10.1007/s00432-021-03616-4. Epub 2021 Apr 3.
Undifferentiated pleomorphic sarcoma (UPS) is a sarcoma with a poor prognosis. A clinical trial, SARC028, revealed that treatment with anti-PD-1 drugs was effective against UPS. Studies have reported that UPS expresses PD-L1, sometimes strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained unclear. CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a novel regulator of PD-L1 expression. The positive relationship between PD-L1 and CMTM6 has been reported in several studies. The aim of this study was thus to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6 in this disease.
Fifty-one primary UPS samples were subjected to CMTM6 and PD-L1 immunostaining. CMTM6 expression was assessed using proportion and intensity scores. CMTM6 gene copy number was also evaluated using a real-time PCR-based copy number assay. We also analyzed the mRNA expression and copy number variation of PD-L1 and CMTM6 in The Cancer Genome Atlas (TCGA) data.
TCGA data indicated that the mRNAs encoded by genes located around 3p22 were coexpressed with CMTM6 mRNA in UPS. Both proportion and intensity scores of CMTM6 positively correlated with strong PD-L1 expression (≥ 50%) (both p = 0.023). CMTM6 copy number gain increased CMTM6 expression. Patients with UPS with a high CMTM6 intensity score had a worse prognosis for overall survival.
UPS showed variation in CMTM6 copy number and CMTM6 expression. CMTM6 expression was significantly correlated with PD-L1 expression, especially with strong PD-L1 expression.
未分化多形性肉瘤（UPS）是一种预后不良的肉瘤。一项临床试验 SARC028 表明，抗 PD-1 药物治疗对 UPS 有效。研究报告称 UPS 表达 PD-L1，有时表达较强（≥50%）。然而，UPS 中 PD-L1 表达的机制仍不清楚。CKLF 样 MARVEL 跨膜结构域包含 6（CMTM6）被鉴定为 PD-L1 表达的新型调节因子。几项研究报告了 PD-L1 与 CMTM6 之间的正相关关系。因此，本研究旨在检测 UPS 中 CMTM6 的表达，并评估 PD-L1 和 CMTM6 在该疾病中的关系。
对 51 例原发性 UPS 样本进行 CMTM6 和 PD-L1 免疫组化染色。使用比例和强度评分评估 CMTM6 表达。还使用基于实时 PCR 的拷贝数测定法评估 CMTM6 基因拷贝数。我们还分析了癌症基因组图谱（TCGA）数据中 PD-L1 和 CMTM6 的 mRNA 表达和拷贝数变异。
TCGA 数据表明，位于 3p22 周围的基因编码的 mRNAs 与 UPS 中的 CMTM6 mRNA 共表达。CMTM6 的比例和强度评分均与强 PD-L1 表达（≥50%）呈正相关（均 p=0.023）。CMTM6 拷贝数增加增加了 CMTM6 的表达。UPS 患者中 CMTM6 强度评分较高者总生存预后较差。
UPS 显示 CMTM6 拷贝数和 CMTM6 表达存在差异。CMTM6 表达与 PD-L1 表达显著相关，尤其是与强 PD-L1 表达相关。
