Association of PD-L1 expression with systemic immune parameters in non-small cell lung cancer.

Background: In non-small cell lung cancer (NSCLC), programmed death-ligand 1 (PD-L1) expression has moderate ability to predict immune checkpoint inhibitor (ICI) benefit. In clinical practice, PD-L1, a cell surface protein, cannot be characterized in currently available blood-based tests such as circulating tumor DNA assays. To understand the biologic effects of PD-L1 more fully and evaluate whether blood-based tests could provide insight into its expression, we determined the association between PD-L1 expression and systemic immune parameters. Methods: We collected pre- and post-treatment (6-week) peripheral blood samples in patients with NSCLC treated with ICI. Using multiplex panels and cytometry by time of flight (CyTOF), we analyzed specimens for baseline and post-treatment changes in cytokines, autoantibodies, and immune cell populations. We determined the association between case characteristics, immune parameters, and tumor PD-L1 expression (categorized as <1%, 1-49%, and ≥50%) using Chi-square, one-way analysis of variance (ANOVA), and Kruskal-Wallis tests, accounting for multiple comparisons. Results: A total of 119 patients were included in the analysis, of whom 41 (34%) had PD-L1 expression <1%; 44 (37%), 1-49%; and 34 (29%), ≥50%. PD-L1 expression was not associated with any demographic, tumor, or treatment characteristics. Among 39 cytokines evaluated, baseline levels of macrophage migration inhibitory factor (MIF) were significantly greater in high PD-L1 positive cases. Among 124 autoantibodies included in the analysis, three (anti-aggrecan, -proteoglycan, and -nucleosome) demonstrated significantly greater post-ICI treatment increases in cases with higher PD-L1 expression. In PD-L1 positive cases, baseline abundance of natural killer T (NKT) cells (P=0.001) and activated monocytes (P=0.04) were significantly lower, while post-treatment increases in mature natural killer (NK) cells were significantly greater (P=0.006). Conclusions: NSCLC PD-L1 expression is associated with few systemic immune parameters, suggesting that effects on anti-tumor immunity may occur predominantly in the tumor microenvironment and that blood-based assays are unlikely to provide meaningful surrogates of this biomarker.