Hui Xue1#, Bin Qiu1#, Hao Wang1, Ping Jiang1, Weiwei Zhang1, Lixiang Xue1,2* and Junjie Wang1*
1Department of Radiation Oncology, Peking University Third Hospital, China
2Medical Research Center, Peking University Third Hospital, China
#These authors contributed equally to this work
Background: CMTM6 and CMTM4 have been described as PD-L1 regulators at the protein level that modulates stability via ubiquitination, but little is known proteins expression and modulation in human gliomas and tumor microenvironment. Clinical trials of targeting PD-1/PD-L1 in glioma have been initiated; however, the rate of objective response has been less than 30% while the rate of complete response has less than 16% due to inadequate T-cell infiltration and immunosuppressive microenvironment. The aim of this study is to investigate the relationship between CMTM6/CMTM4 and PD-L1 expression and its association with clinical prognosis in gliomas.
Materials and Methods: The expression of CMTM6/CMTM4 and PD-L1 in 177 glioma samples represented in tissue microarrays was determined by Multiplexed quantitative immunofluorescence. The assessment of the relationship between clinical factors and CMTM6/CMTM4 expression was analyzed by Chi-squared test. The assessment of the clinical factors associated with survival
was analyzed by univariate and multivariate Cox proportional hazard regression analyses. The evaluation of the statistical significance was analyzed by Pearson’s correlation assessment. The survival probability was analyzed by Kaplan-Meier survival analysis and log-rank test. Results: In gliomas, CMTM6/CMTM4 and PD-L1 were colocalized in tumor (Ki67+) and microenvironment (CD68+ macrophages). CMTM6 was significantly related to PD-L1. Similarly, CMTM4 was significantly related to PD-L1. Meanwhile, CMTM6 was significantly related to CMTM4. CMTM6/CMTM4 showed a modest correlation with CD8+ T cell infiltration. Surprisingly, CMTM6 was associated with clinical factors related to recurrence and Ki67. CMTM4 expression showed a significant correlation with Ki67. CMTM6 was a risk factor for prognosis. Finally, we found that patients with high CMTM6/CMTM4/PD-L1 expression showed shorter OS than those with low expression. What is more, OS was significantly longer when CMTM6/CMTM4 and PDL1 were high co-expression in macrophages, but OS did not obviously extended in patients whose tumors had high CMTM6/CMTM4 single expression in macrophages. Conclusion: This study supports the role of CMTM6 and CMTM4 in stabilization of PD-L1 protein and suggests that high co-expression of CMTM6/CMTM4 and PD-L1 in macrophages might be prognosis indicators for anti-PD-L1 therapy in gliomas.
CMTM6; CMTM4; PD-L1; Macrophages; Gliomas
Xue H, Qiu B, Wang H, Jiang P, Zhang W, Xue L, et al. Analysis of CMTM6 and CMTM4 Expression as Potential Regulators of the PD-L1 Protein and its Association with Prognosis in Gliomas. Clin Oncol. 2022;7:1897..