Clinical roles of soluble PD-1 and PD-L1 in plasma of NSCLC patients treated with immune checkpoint inhibitors

Introduction: Immune checkpoint inhibitors (ICI) have significantly improved the prognosis of non-small cell lung cancer (NSCLC). However, only a limited proportion of patients can benefit from this therapy, and clinically useful predictive biomarkers remain to be elucidated. Methods Blood was collected from 189 patients with NSCLC before and six weeks after the initiation of the ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Soluble PD-1 (sPD-1) and PD-L1 (sPD-L1) in plasma before and after treatment were analyzed for evaluation of their clinical significance. Results The Cox regression analysis demonstrated that higher sPD-L1 levels before treatment significantly predicted unfavorable progression-free survival (PFS; HR 15.4, 95%CI 1.10–86.7, P = 0.009) and overall survival (OS; HR 11.4, 95%CI 1.19–52.3, P = 0.007) in NSCLC patients treated with ICI monotherapy (n = 122), but not in those treated with ICI combined with chemotherapy (n = 67: P = 0.729 and P = 0.155, respectively). In addition, higher sPD-1 levels after treatment were significantly associated with better OS (HR 0.24, 95%CI 0.06–0.91, P = 0.037) in patients treated with anti-PD-1 monotherapy, whereas higher sPD-L1 levels after treatment were significantly associated with worse PFS (HR 6.09, 95%CI 1.42–21.0, P = 0.008) and OS (HR 42.6, 95%CI 6.83–226, P < 0.001). The levels of sPD-L1 at baseline were well correlated with those of other soluble factors, such as sCD30, IL-2Ra, sTNF-R1, and sTNF-R2, which are known to be released from the cell surface by zinc-binding proteases ADAM10/17. Conclusions These findings suggest the clinical significance of pre-treatment sPD-L1 as well as post-treatment sPD-1 and sPD-L1 in NSCLC patients treated with ICI monotherapy.