An immunophenotyping of renal clear cell carcinoma with characteristics and a potential therapeutic target for patients insensitive to immune checkpoint blockade. Issue 8 (27th March 2019)

• Record Type: Journal Article
• Authors: Zhao, Weiwei; Zhao, Falin; Yang, Kai; Lu, Yaxin; Zhang, Yuanyuan; Wang, Wenjie; Xie, Hongyu; Deng, Kui; Yang, Chunyan; Rong, Zhiwei; Hou, Yan; Li, Kang
• Is Part Of: Journal of cellular biochemistry. Volume 120:Issue 8(2019)
• Page Start: 13330
• Page End: 13341
• Publication Date: 2019-03-27
• Subjects: CD274 -- CMTM6 -- immune checkpoint blockade -- immunophenotyping -- renal clear cell carcinoma; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.28607
• Languages: English
• ISSNs: 0730-2312

Abstract

Abstract: 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. Abstract : We identified three immune molecular subtypes of renal clear cell carcinoma (RCC) patients with different sensitivity to immune checkpoint blockade (ICB) based on PD‐1/PD‐L1 and CTLA‐4 pathways, as well as two new regulators CMTM6 and CMTM4. Together, the interaction between CMTM6 and PD‐L1 was identified, indicating that the function of PD‐L1 was influenced by CMTM6. This study makes for studies about identifying ICB sensitivity group and offers a potential therapeutic target for ICB‐insensitive group.