Soluble immune checkpoint-related proteins as predictors of tumor recurrence, survival, and T cell phenotypes in clear cell renal cell carcinoma patients

Abstract

BackgroundImmune 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.MethodsWe 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.ResultssTIM3 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).ConclusionsOur 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.

Early Change in the Plasma Levels of Circulating Soluble Immune Checkpoint Proteins in Patients with Unresectable Hepatocellular Carcinoma Treated by Lenvatinib or Transcatheter Arterial Chemoembolization

“…Elsewhere, CD40 and HVEM messenger RNAs were coexpressed in the bioinformatic analysis of bladder cancer in the Cancer Genome Atlas database [47]. HVEM is a ligand of B-and T-lymphocyte attenuator (BTLA) and soluble BTLA in combination with sTIM-3 may be able to predict the rates of disease recurrence and survival among renal cell cancer patients [48].…”

LAG3(LAG-3,CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma

“…39 Furthermore, soluble LAG3, which is known to function as a dendritic cell activator, was also recently shown to be associated with advanced KIRC stage. 40 Tumor-specific LAG3 upregulation might be an immune evasion phenotype similarly to PD-L1 upregulation or upregulation of other immune checkpoints. This hypothesis needs further functional evaluation.…”

The Evolving Landscape of PD-1/PD-L1 Pathway in Head and Neck Cancer

“…Moreover, PD-L1 is also expressed in non-immune cells, such as cornea cells, vascular endothelial cells, mesenchymal stem cells, and keratinocytes, and it is often inducibly or constitutively upregulated on tumor cells of lots of solid and hematologic tumors (20). Interestingly, PD-L1 has been found in a soluble form (sPD-L1) in the patients' serum with tumors, such as melanoma and lung adenocarcinoma (22)(23)(24)(25). Theodoraki et al also demonstrated that sPD-L1 was found in plasma of patients with HNSCC (26).…”