Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, People's Republic of China.
Department of Health Management, School of Medicine, Hangzhou Normal University, Hangzhou, People's Republic of China.
J Cell Biochem. 2019 Aug;120(8):13330-13341. doi: 10.1002/jcb.28607. Epub 2019 Mar 27.
Renal clear cell carcinoma (RCC) patients who do not achieve optimal control of progression with immune checkpoint blockade (ICB) should be further studied. Unsupervised consensus clustering was used to group 525 RCC patients based on two typical ICB pathways, CTLA-4 and pogrammed death 1 (PD-1)/programmed death-ligand 1 (PD-L1), as well as two new discovered regulators, CMTM6 and CMTM4. Three immune molecular subtypes (IMMSs) with different clinical and immunological characteristics were identified (type I, II, and III), among which there were more stage I and low-grade tumors in type I RCC than in type II and III. The proportion of males was highest in type II RCC. Overall survival of type II and III was similar (5.2 and 6 years) and statistically shorter than that of type I (7.6 years) before and after adjusting for age and gender. When conducting stratified analysis, our IMMSs were able to identify high-risk patients among middle-aged patients, males, and stage IV patients. Among the differentially expressed genes, approximately 84% were highly expressed in type II and III RCC. Genes related to ICB (CTLA-4, CD274, and PDCD1LG2) and cytotoxic lymphocytes (CD8A, GZMA, and PRF1) were all highly expressed in type II and III RCC. These results documented that patients with type II and III cancer may be more sensitive to anti-CTLA-4 therapy, anti-PD-1/PD-L1 therapy, and a combination of immunotherapies. High expression of CMTM4 in type I RCC (69%) and a statistically significant interaction of CD274 and CMTM6 indicated that CMTM4/6 might be new therapy targets for type I, who are resistant to ICB.
对于未通过免疫检查点阻断（ICB）实现进展最佳控制的肾透明细胞癌（RCC）患者，应进一步研究。使用无监督共识聚类法，根据两种典型的 ICB 途径（细胞毒性 T 淋巴细胞相关抗原 4 [CTLA-4] 和程序性死亡受体 1 [PD-1]/程序性死亡配体 1 [PD-L1]）以及两个新发现的调节剂，细胞运动蛋白 6（CMTM6）和细胞运动蛋白 4（CMTM4），对 525 例 RCC 患者进行分组。确定了具有不同临床和免疫学特征的三种免疫分子亚型（IMMS）（I 型、II 型和 III 型），其中 I 型 RCC 的 I 期和低级别肿瘤比例高于 II 型和 III 型。II 型 RCC 中男性比例最高。在调整年龄和性别后，II 型和 III 型的总生存期（OS）相似（5.2 和 6 年），且明显短于 I 型（7.6 年）。分层分析时，我们的 IMMS 能够在中年患者、男性和 IV 期患者中识别高危患者。在差异表达基因中，大约 84%在 II 型和 III 型 RCC 中高表达。与 ICB 相关的基因（CTLA-4、CD274 和 PDCD1LG2）和细胞毒性淋巴细胞（CD8A、GZMA 和 PRF1）在 II 型和 III 型 RCC 中均高表达。这些结果表明，II 型和 III 型癌症患者可能对抗 CTLA-4 治疗、抗 PD-1/PD-L1 治疗以及免疫治疗联合治疗更敏感。I 型 RCC 中 CMTM4 高表达（69%）以及 CD274 和 CMTM6 的统计学显著相互作用表明，CMTM4/6 可能是对 ICB 耐药的 I 型的新治疗靶点。
