Immune checkpoint inhibitors have achieved unprecedented success in cancer immunotherapy. With the exception of a few candidate biomarkers, the prognostic role of soluble immune checkpoint-related proteins in clear cell renal cell cancer (ccRCC) patients is largely uninvestigated.
We profiled the circulating levels of 14 immune checkpoint-related proteins panel (BTLA, GITR, HVEM, IDO, LAG-3, PD-1, PD-L1, PD-L2, Tim-3, CD28, CD80, CD137, CD27 and CTLA-4) and their associations with the risk of recurrence and death in 182 ccRCC patients using a multiplex Luminex assay. Gene expression in tumors from a subset of participating patients (n = 47) and another 533 primary ccRCC from TCGA were analyzed to elucidate potential mechanisms. Our primary endpoint is overall survival; secondary endpoint is recurrence-free survival. Multivariate Cox proportional hazard model, unconditional logistic regression model, and Kaplan-Meier analysis were applied in the study.
sTIM3 and sLAG3 were significantly associated with advanced (stage III) disease (P < 0.05). sPD-L2 was the strongest predictor of recurrence (HR 2.51, 95%CI 1.46-4.34, P = 9.33E-04), whereas high sBTLA and sTIM3 was associated with decreased survival (HR 6.02, 95%CI 2.0-18.1, P = 1.39E-03 and HR 3.12, 95%CI 1.44-6.75, P = 3.94E-03, respectively). Risk scores based on sTIM3 and sBTLA indicated that the soluble immune checkpoint-related proteins jointly predicted recurrence and death risks of ccRCC (P = 0.01 and 4.44E-04, respectively). Moreover, sLAG3 and sCD28 were found negatively correlated with cytolytic activity of T cells in tumors (rho = -0.31 and - 0.33, respectively).
Our study provides evidence that soluble immune checkpoint-related proteins may associate with advanced disease, recurrence and survival in ccRCC patients, which highlights the prognostic values of soluble immune checkpoint-related proteins. Future independent validation in prospective studies is warranted.
Journal for immunotherapy of cancer. 2019 Nov 29*** epublish ***
Qinchuan Wang, Jinhua Zhang, Huakang Tu, Dong Liang, David W Chang, Yuanqing Ye, Xifeng Wu
Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital and Department of Epidemiology and Health Statistics School of Public Health, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China., Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Pharmaceutical Sciences, Texas Southern University, Houston, TX, USA., Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. .