Differential expression of PD‑L1 and PD‑L2 is associated with the tumor microenvironment of TILs and M2 TAMs and tumor differentiation in non‑small cell lung cancer.

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 both tumor cells (TCs) and tumor‑infiltrating immune cells (ICs) was investigated, with respect to tumor‑infiltrating lymphocytes (TILs) and M2 tumor‑associated macrophages (TAMs), which are key components of the tumor microenvironment, in 175 patients with resected NSCLC. The TIL and M2 TAM densities were associated with the expression of PD‑L1 on the two TCs (both P<0.0001) and ICs (both P<0.0001). The TIL and M2 TAM densities were also associated with the expression of PD‑L2 on both TCs (P=0.0494 and P=0.0452, respectively) and ICs (P=0.0048 and P=0.0125, respectively). 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 the PD‑L1 expression on TCs and ICs (P=0.0002 and P<0.0001, respectively). By contrast, tumor differentiation was inversely associated with the PD‑L2 expression on both TCs and ICs (P=0.0260 and P=0.0326, respectively). In conclusion, 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.