Clinical significance of PD-1-binding soluble PD-L1 and MMPs in the microenvironment of gastric cancer and non-small cell lung cancer treated with PD-1/PD-L1 blockade

Abstract

AbstractPurposeThe tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade.Experimental DesignWe examined bsPD-L1, matrix metalloproteinases (MMPs), and IFN-γ levels in plasma samples from GC patients (n =117) prior to surgery and NSCLC patients (n =72) prior to and two months after ICI treatment and extracellular matrix (ECM) integrity, PD-L1 expression, and T cell infiltration in tumor tissues from 25 GC patients.ResultsbsPD-L1 was detected in 17/117 GC patients and 16/72 NSCLC patients. bsPD-L1 was strongly and moderately correlated with MMP13 and MMP3, respectively. In GC, bsPD-L1 expression was associated with IFN-γ levels and intra-tumoral T cell infiltration; MMP13 levels were associated with loss of ECM integrity, allowing tumor cells to access blood vessels. MMP3 and MMP13 levels were altered during ICI treatment. Combination of bsPD-L1 and MMP levels identified two patient groups; bsPD-L1+MMP13highin GC and bsPD-L1+(MMP3 and MMP13)increasedin NSCLC were associated with poor prognosis, and bsPD-L1+MMP13lowin GC and bsPD-L1+(MMP3 or MMP13)decreasedin NSCLC were associated with favorable prognosis.ConclusionsPlasma bsPD-L1 and MMP13 levels indicate T cell response and loss of ECM integrity, respectively, in the TME. The combination of bsPD-L1 and MMPs may represent a non-invasive tool to predict recurrence in GC and the efficacy of ICIs in NSCLC.