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.