Stromal PD-1⁺ tumor-associated macrophages predict poor prognosis in lung adenocarcinoma

Immunotherapies targeting programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1) axis have been emerging as a promising therapeutic strategy to treat lung cancer. PD-1 is preferentially expressed by activated T lymphocytes; but whether/how its expression by tumor-associated macrophages (TAMs) in lung adenocarcinoma remains elusive. Herein, we investigate the frequency of PD-1 expression on TAMs in mouse allografts by flow cytometry analysis and evaluate the spatial distribution and clinicopathological significance of PD-1⁺ TAMs in 213 cases of human lung adenocarcinoma specimens by immunohistochemical staining. We find the expression of PD-1 by both mouse and human TAMs. Mouse PD-1⁺ TAMs possess unique transcriptional profile as compared to PD-1^- TAMs. Furthermore, PD-1 is preferentially expressed by CD163⁺ TAMs in the tumor stroma than those in the tumor islets of lung adenocarcinoma. Stromal PD-1⁺ TAM infiltration is an independent predictor of reduced survival as determined by univariate (P < .001) and multivariate (P = .023) analysis. Moreover, patients with high stromal PD-1⁺ TAMs but low tumor cell PD-L1 expression have the shortest survival (P = .0001). Our study demonstrates that PD-1⁺ TAMs have unique gene expression characteristics and PD-1⁺ TAMs in the tumor stroma is a potential prognostic factor in lung adenocarcinoma, suggesting that a better understanding of PD-1⁺ TAMs will be beneficial for immunotherapy of lung adenocarcinoma patients.