M1-like TAMs are required for the efficacy of PD-L1/PD-1 blockades in gastric cancer

The efficacy of PD-1/PD-L1 blockades is heterogeneous in different molecular subtypes of gastric cancer (GC). In this study, we analyzed relevant clinical trials to identify the molecular subtypes associated with the efficacy of PD-1/PD-L1 blockades, and public datasets, patient samples, and GC cell...

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Veröffentlicht in:Oncoimmunology Jg. 10; H. 1; S. 1862520
Hauptverfasser: Zhao, Rui, Wan, Qianyi, Wang, Yong, Wu, Yutao, Xiao, Shuomeng, Li, Qiqi, Shen, Xiaoding, Zhuang, Wen, Zhou, Yong, Xia, Lin, Song, Yinghan, Chen, Yi, Yang, Hanshuo, Wu, Xiaoting
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Taylor & Francis 01.01.2021
Taylor & Francis Group
Schlagworte:
gastric cancer
Original Research
PD-L1/PD-1 blockades
Tumor-associated macrophages
gastric cancer
PD-L1/PD-1 blockades
Tumor-associated macrophages
ISSN:2162-402X, 2162-4011, 2162-402X
Online-Zugang:Volltext
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Zusammenfassung:The efficacy of PD-1/PD-L1 blockades is heterogeneous in different molecular subtypes of gastric cancer (GC). In this study, we analyzed relevant clinical trials to identify the molecular subtypes associated with the efficacy of PD-1/PD-L1 blockades, and public datasets, patient samples, and GC cell lines were used for investigating potential mechanisms. We found that GC with EBV-positive, MSI-H/dMMR, TMB-H or PIK3CA mutant subtype had enhanced efficacy of PD-L1/PD-1 blockades. Also, differentially expressed genes of these molecular subtypes shared the same gene signature and functional annotations related to immunity. Meanwhile, CIBERSORT identified that the overlapping landscapes of tumor-infiltrating immune cells in the four molecular subtypes were mainly M1-like macrophages (M1). The relationships between M1 and clinical characteristics, M1, and gene signatures associated with PD-1/PD-L1 blockades also revealed that M1 was associated with improved prognosis and required for the efficacy of PD-L1/PD-1 blockades in GC. We identified that tumor-infiltrating CD68 + CD163 − macrophages could represent M1 calculated by CIBERSORT in clinical application, and CXCL9, 10, 11/CXCR3 axis was involved in the mechanism of CD68 + CD163 − macrophages in the enhanced efficacy of PD-L1/PD-1 blockades. In conclusion, CD68 + CD163 − macrophages are required for the efficacy of PD-L1/PD-1 blockades and expand the applicable candidates in GC patients without the molecular subtypes.
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Rui Zhao, Qianyi Wan, and Yong Wang contributed equally to this study.
ISSN:2162-402X
2162-4011
2162-402X
DOI:10.1080/2162402X.2020.1862520