Abstract 5829: Differential expression of PD-L1 and PD-L2 is associated with M2 tumor-associated macrophages and tumor differentiation in non-small cell lung cancer

Abstract Objectives: To improve the treatment strategy of immune-checkpoint inhibitors for non-small cell lung cancer (NSCLC), a comprehensive analysis of programmed death-ligand (PD-L)1 and PD-L2 expression is clinically important. The expression of PD-L1 and PD-L2 on tumor cells (TCs) and tumor-infiltrating immune cells (ICs) was investigated with respect to M2 tumor-associated macrophages (TAMs), which are key components of the tumor microenvironment. Methods: We performed immunohistochemical studies to evaluate the M2 TAM distribution by CD163 staining, PD-L1 expression on TCs and ICs by the Ventana SP263 assay, and PD-L2 expression on TCs and ICs, using the Ventana BenchMark GX system, in 175 patients with resected NSCLC. Results: M2 TAM density revealed high levels of variation among the 175 tumor tissues (mean ± standard deviation (SD), 382.5 ± 381.9 cells per mm2). The percentage of PD-L1-positive TCs and PD-L1-positive ICs varied greatly among the 175 tumor tissues (mean ± SD; 15.6 ± 27.0% and 9.4 ± 10.9%, respectively). In addition, the percentage of PD-L2-positive TCs and PD-L2-positive ICs also ranged widely among the 175 tumor tissues (mean ± SD, 14.6 ± 22.9% and 12.5 ± 18.4%, respectively). M2 TAM density was significantly associated with the expression of PD-L1 on TCs and ICs (P < 0.0001 and P < 0.0001, respectively). M2 TAM density was also significantly associated with the expression of PD-L2 on TCs and ICs (P = 0.0452 and P = 0.0125, respectively). The percentage of PD-L1-positive TCs was significantly correlated with the percentage of PD-L1-positive ICs (r = 0.396; P < 0.0001). In addition, the percentage of PD-L2-positive TCs also was significantly correlated with the percentage of PD-L2-positive ICs (r = 0.488; P < 0.0001). However, there was no correlation between the percentage of PD-L1-positive TCs and the percentage of PD-L2-positive TCs (r = 0.019; P = 0.8049). Meanwhile, tumor differentiation was significantly associated with PD-L1 expression on TCs and ICs (P = 0.0002 and P < 0.0001, respectively). By contrast, tumor differentiation was inversely associated with PD-L2 expression on TCs and ICs (P = 0.0260 and P = 0.0326, respectively). Conclusions: PD-L1 and PD-L2 expression on TCs and ICs was associated with M2 TAMs in NSCLC, although there was no correlation between PD-L1 and PD-L2 expression on TCs. The combined evaluation of PD-L1 and PD-L2 expression could be clinically important in the treatment strategy of immune-checkpoint inhibitors in patients with NSCLC. In particular, the evaluation of PD-L2 expression may be necessary for patients with PD-L1-negative NSCLC. Citation Format: Ryota Sumitomo, Huang Cheng-long, Hiroshi Date. Differential expression of PD-L1 and PD-L2 is associated with M2 tumor-associated macrophages and tumor differentiation in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5829.