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Tumor‑associated macrophages (TAMs), particularly M2 macrophages, promote tumor progression, while Wnt genes encode a family of multi‑functional glycoproteins that serve an important role in tumorigenesis. Immunohistochemical studies were performed to evaluate Wnt2b and Wnt5a expression in tumor and stromal cells in M2 and M1 TAMs and Ki‑67 proliferation index in 160 consecutive patients with resected non‑small cell lung cancer (NSCLC). Overall, 52 tumors (32.5%) were classified as tumoral Wnt2b‑high (Wnt2b‑positive tumor cells >30%) and 95 (59.4%) as stromal Wnt2b‑high (Wnt2b‑positive stromal cells >30%), while 75 (46.9%) were classified as tumoral Wnt5a‑high (Wnt5a‑positive tumor cells >30%) and 63 (39.4%) as stromal Wnt5a‑high (Wnt5a‑positive stromal cells >28%). The density of M2 TAMs was significantly higher in the tumoral (P=0.0024) and stromal Wnt2b‑high groups (P=0.0054). The density of M2 TAMs was also significantly higher in the tumoral (P=0.0005) and stromal Wnt5a‑high groups (P=0.0486). By contrast, no difference in stromal or islet M1 TAM density was observed in relation to tumoral or stromal Wnt2b or Wnt5a status. Furthermore, Ki‑67 proliferation index was significantly higher in the tumoral (P=0.0121) and stromal Wnt2b‑high (P=0.0019) and tumoral Wnt5a‑high (P=0.0088) groups. Overall survival rate was significantly lower in the Wnt2b‑high (P=0.0437), Wnt5a‑high (P=0.0106) and M2 TAM‑high (P=0.0060) groups. Wnt2b and Wnt5a expression in tumor and stromal cells may induce M2 TAMs to produce more aggressive behavior during tumor progression in NSCLC.

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.