Classification of PD-L1 expression in various cancers and macrophages based on immunohistocytological analysis

Programmed death (PD)-1/PD-ligand 1 (PD-L1) antibodies have shown an intense clinical effect in some patients with PD-L1⁺ tumors, and their applications have rapidly expanded to various cancer types with or without the application of new companion diagnostics (CDx) with a lower cutoff value and inclusion of macrophage evaluation. However, the pathological background explaining the difference in the cutoff value remains unknown. To address this, we evaluated tissue array samples from 231 patients with lung adenocarcinoma, 186 with lung squamous cell carcinoma, and 38 with renal cell carcinoma (RCC) who were not receiving PD-1/PD-L1 antibodies to investigate the relationship between PD-L1 expression on tumor cells and CD8⁺ T-cell infiltration in tumor tissues. PD-L1 expression in RCC was clearly lower than that in non-small-cell lung cancer (NSCLC) tissue, whereas CD8⁺ T-cell infiltration was low in all cancers. We next analyzed PD-L1 expression by interferon (α, β, and γ) and LPS stimulation in both macrophages and 41 cancer cell lines derived from various organs and histological types. The PD-L1 expression patterns were classified into three types, which differed depending on each organ or tissue type. Interestingly, NSCLC cell lines showed highly diverse PD-L1 expression patterns compared with RCC cell lines. Conversely, PD-L1 expression was stronger and more prolonged in macrophages than in typical cell lines. Here, we revealed the diversity of the PD-L1 expression patterns in tumor cells and macrophages, demonstrating the pathological and cytological significance of the transition of cutoff values in PD-L1 CDx for PD-1/PD-L1 antibody administration.