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M2 macrophage infiltration into tumor islets leads to poor prognosis in non-small-cell lung cancer

Authors Cao L, Che X, Qiu X, Li Z, Yang B, Wang S, Hou K, Fan Y, Qu X, Liu Y

Received 29 December 2018

Accepted for publication 10 May 2019

Published 4 July 2019 Volume 2019:11 Pages 6125—6138


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Beicheng Sun

Lili Cao,*,1,2 Xiaofang Che,*,1,2 Xueshan Qiu,3 Zhi Li1,2 Bowen Yang1,2 Shuo Wang1,2 Kezuo Hou1,2 Yibo Fan1,2 Xiujuan Qu1,2 Yunpeng Liu1,2

1Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 2Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 3Department of Pathology, College of Basic Medical Sciences of China Medical University, Shenyang 110001, People’s Republic of China

*These authors contributed equally to this work

Background: Lung cancer is the leading cause of cancer-related death worldwide. Although the macrophages can affect the development of tumor, the contribution of macrophages to the prognosis of non-small-cell lung cancer (NSCLC) is still controversial. Moreover, anti-PD-1 therapy can redirect macrophages from an M2 to an M1 phenotype, suggesting that tumor PD-L1 may affect the prognostic role of macrophages. Therefore, in this study, we aimed to display a macrophage landscape to clarify the function of macrophages, considering the localization and polarization of the macrophages, and evaluate the effect of M2 macrophages and tumor PD-L1 in combination on the prognosis of NSCLC.
Methods: We performed multiplex quantitative immunofluorescence staining of pan-cytokeratin (CK), CD68, CD163, PD-L1, and DAPI on one tissue specimen simultaneously from 137 NSCLC patients.
Results: M2 macrophages, involved marginM2 (M2 macrophages in tumor stroma), and centralM2 (M2 macrophages infiltrating into tumor islets) increased as the tumor stage increased. More macrophages were found in lung squamous cell carcinoma (LUSC) patients, patients with wild-type EGFR, and smokers than in patients with lung adenocarcinoma (LUAD), patients with EGFR mutations, and non-smokers. Infiltration of centralM2 was an independent prognostic factor of poor overall survival (OS) and disease-free survival (DFS) for NSCLC patients (P<0.05), which was superior to total macrophages and total M2 macrophages. Moreover, patients with centralM2less,PD-L1−, tumors showed the best OS and DFS, while the patients with centralM2more,PD-L1+, tumors showed the worst OS and DFS, and the two groups with centralM2less,PD-L1+, and centralM2more,PD-L1−, were in the middle (P=0.002, 0.034, respectively).
Conclusion: Tumor islet-infiltrating M2 macrophages influence the prognosis of NSCLC patients. The analysis of M2 macrophages and tumor PD-L1 in combination may enhance the accuracy of prognostic prediction. This study provides a new understanding of macrophages in the development of NSCLC through the analysis of macrophage landscape.

Keywords: macrophage, microenvironment, polarization, non-small-cell lung cancer, prognosis, PD-L1

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