The integration of systemic and tumor PD-L1 as a predictive biomarker of clinical outcomes in patients with advanced NSCLC treated with PD-(L)1blockade agents

Abstract

Background: Tumor PD-L1 expression is a predictive biomarker for patients with NSCLC receiving PD-(L)1 blockade agents. However, although increased tumor PD-L1 expression predicts responsiveness, clinical benefit has been observed regardless of tumor PD-L1 expression, suggesting the existence of other PD-L1 sources. The aim of our study was to analyze whether integrating systemic and tumor PD-L1 is more predictive of efficacy in patients with advanced NSCLC receiving PD-(L)1 blockade agents.

Material and methods: Twenty-nine healthy donors and 119 consecutive patients with advanced NSCLC treated with PD-(L)1 drug were prospectively included. Pretreatment blood samples were collected to evaluate PD-L1 levels on circulating immune cells, platelets (PLTs), platelet microparticles (PMPs), and the plasma soluble PD-L1 concentration (sPD-L1). Tumor PD-L1 status was assessed by immunohistochemistry. The percentages of circulating PD-L1 + leukocytes, sPD-L1 levels, and tumor PD-L1 were correlated with efficacy.

Results: No differences in the percentages of circulating PD-L1 + leukocytes were observed according to tumor PD-L1 expression. Significantly longer progression-free survival was observed in patients with higher percentages of PD-L1 + CD14 + , PD-L1 + neutrophils, PD-L1 + PLTs, and PD-L1 + PMPs and significantly longer overall survival was observed in patients with higher percentages of PD-L1 + CD14 + and high tumor PD-L1 expression. Integrating the PD-L1 data of circulating and tumor PD-L1 results significantly stratified patients according to the efficacy of PD-(L1) blockade agents.

Conclusions: Our results suggest that integrating circulating PD-L1 + leukocytes, PLT, PMPs, and sPD-L1 and tumor PD-L1 expression may be helpful to decide on the best treatment strategy in patients with advanced NSCLC who are candidates for PD-(L)1 blockade agents.

Keywords: Immunotherapy; NSCLC; Predictive biomarker; Soluble PD-L1; Systemic PD-L1.

Fig. 1

Percentage of baseline circulating PD-L1 + leukocytes, PD-L1 + PLTs and PMPs and plasma sPD-L1 levels in patients with advanced NSCLC and HD prior to PD-(L)1 therapy. a Representative image of PD-L1 expression (PD-L1 +) on circulating CD4 + and CD8 + T lymphocytes, CD8 + NK cells, CD14 + monocytes, Neutrophils, platelets (PLTs), and platelets microparticles (PMPs) from HD and patients with NSCLC. b Dot plots show the percentage of circulating PD-L1 + leukocytes subpopulations (HD and 119 patients with NSCLC), PLTs and PMPs (HD and 76 patients with NSCLC), and c plasma soluble PD-L1 (sPD-L1) levels (HD and 118 NSCLC patients). * p < 0.05, **p < 0.01 and ***p < 0.001

Fig. 2

Percentage of circulating PD-L1 + leukocytes, PD-L1 + PLTs and PMPs, and plasma sPD-L1 levels according to tumor PD-L1 expression. Dot plots show percentage of a PDL1 + CD4 + , PD-L1 + CD8 + and PD-L1 + CD8 + NK cells (102 patients with NSCLC), b PD-L1 + CD14 + and PD-L1 + Neutrophils (102 patients with NSCLC), c Platelets (PLTs) and platelets microparticles (PMPs) (73 patients with NSCLC) and d plasma soluble PD-L1 (sPD-L1) (101 patients with NSCLC) according to PD-L1 tumor expression (TPS: tumor proportion score)

Fig. 3

Median progression-free survival comparing high and low percentage of PD-L1 + leukocytes, PD-L1 + PLTs and PMPs, plasma sPD-L1 levels, and tumor PD-L1 expression. Median progression-free survival (PFS) according to high or low group of a PD-L1 + CD4 + , b PD-L1 + CD8 + , c PD-L1 + CD8 + NK cells, d PD-L1 + CD14 + , e PD-L1 + Neutrophils, f pg/ml of sPD-L1, g PD-L1 + PLTs and h PD-L1 + PMPs. i tumor proportion score (TPS)

Fig. 4

Median overall survival comparing high and low percentage of PD-L1 + leukocytes, PD-L1 + PLTs and PMPs, plasma sPD-L1 levels, and tumor PD-L1 expression. Median progression-free survival (PFS) according to high or low group of a PD-L1 + CD4 + , b PD-L1 + CD8 + , c PD-L1 + CD8 + NK cells, d PD-L1 + CD14 + , e PD-L1 + Neutrophils, f pg/ml of sPD-L1, g PD-L1 + PLTs and h PD-L1 + PMPs. i Tumor proportion score (TPS)

Fig. 5

Median progression-free survival (PFS) and overall survival (OS) in different groups of patients with NSCLC achieved according to the integration of PD-L1 data (IPD) from different systemic and tumor sources. a ROC curve comparing the integrated PD-L1 data (IPD) from systemic and tumor PD-L1 sources (leukocytes, PLTs and PMPs, sPD-L1 and TPS) from patients with progressive versus non-progressive disease to PD-(L)1 blockade agents to obtain the best cut-off point to discriminate them. b MedianPFS and c median OS according to the cut-off point (154.1). d ROC curve comparing the IPD from PD-L1 + CD14 + and tumor PD-L1 expression from patients with progressive versus non-progressive disease to PD-(L)1 blockade agents. e Median PFS and f median OS according to the cut-off point (83.85). g ROC curve comparing the IPD from PD-L1 + leukocytes, PD-L1 + PLTs and PMPs and plasma sPD-L1 levels from patients with progressive versus non-progressive disease to PD-(L)1 blockade agents. h Median PFS and i median OS according to the cut-off point (105)

Fig. 6

A model of the systemic and local PD-L1 sources in patients with advanced NSCLC. The PD-L1 sources that we have associated with the clinical outcome of patients with advanced NSCLC treated with anti-PD-(L)1 blockade agents are highlighted with color squares. We found that higher percentages of PD-L1 + monocytes were associated with longer PFS and OS, higher percentages of PD-L1 + neutrophils, PLTs, and PMPs with PFS, and higher percentages of PD-L1 + tumor cells with OS. Figure created with Biorender.com