Soluble immune checkpoints proteins are significantly associated with the susceptibility of renal cell cancer, a case–control study

Cancer immunotherapy has profoundly reshaped treatment strategies for renal cell cancer (RCC). However, the role of soluble immune checkpoint proteins in RCC patients remains unclear. We utilized multiplex Luminex method to assess the circulating levels of 14 immune checkpoints (TIM-3, CD28, CD80, CD137, CD27, CTLA-4, BTLA, GITR, HVEM, IDO, LAG-3, PD-1, PD-L1, and PD-L2) in 40 RCC patients and 40 healthy controls. A multivariate logistic regression was employed to construct a diagnostic model for RCC. The performance of the diagnostic model was evaluated using ROC curves. Gene expression of the immune checkpoint related proteins in tumor tissues and normal tissues from TCGA and GEO was analyzed for functional exploration. Compared to healthy controls, the median levels of sCTLA-4, sLAG-3, sBTLA, sGITR, sCD80, and sPD-1 were significantly elevated in the RCC patients. Higher levels of sCTLA-4 (OR = 1.91, 95%CI: 1.18–3.09, P = 0.008) and sHVEM (OR = 1.22, 95%CI: 1.01–1.48, P = 0.048) were associated with an increased RCC risk, while sCD28 (OR = 0.93, 95%CI: 0.88–0.98, P = 0.011) was associated with a decreased RCC risk. The soluble immune checkpoint (SIC) score, based on sCTLA-4, sHVEM, and sCD28, was significantly associated with increased RCC risk (OR = 1.55, 95% CI: 1.18–2.16, P < 0.05). The combined model integrating the SIC score and clinical variables showed moderate discriminative ability (AUC = 0.86, 95% CI 0.78–0.94). Furthermore, the upregulation of IDO1 (IDO) and TNFRSF14 (HVEM) was associated with the tumorigenesis and development of RCC in both TCGA and GEO datasets, while the upregulation of PDCD1LG2 (PD-L2) was correlated with the tumorigenesis and development of RCC. Our exploratory findings indicate a potential association between soluble immune checkpoint proteins and the risk of RCC, highlighting the need for future prospective studies to explore their role in disease screening of RCC.