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-I 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 stromai PD-1(+) TAMs but low tumor cell PD-Ll 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. (C) 2020 Elsevier Inc. All rights reserved.