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- Title
The local immune landscape determines tumor PD-L1 heterogeneity and sensitivity to therapy.
- Authors
Yuan Wei; Qiyi Zhao; Zhiliang Gao; Xiang-Ming Lao; Wei-Ming Lin; Dong-Ping Chen; Ming Mu; Chun-Xiang Huang; Zheng-Yu Liu; Bo Li; Limin Zheng; Dong-Ming Kuang; Wei, Yuan; Zhao, Qiyi; Gao, Zhiliang; Lao, Xiang-Ming; Lin, Wei-Ming; Chen, Dong-Ping; Mu, Ming; Huang, Chun-Xiang
- Abstract
PD-L1 is a promising therapeutic target in aggressive cancers. However, immune landscapes and cancer hallmarks of human PD-L1+ tumors, as well as their roles in determining therapeutic efficacies are unknown. Here we identified, in detailed studies of gene data regarding 9769 patients of 32 types of human cancers, that PD-L1 could not exclusively represent IFN-γ signature and potentially signified pro-inflammatory myeloid responses in a tumor. PD-L1 heterogeneity endowed by local immune landscapes controlled cancer hallmarks and clinical outcomes of patients. Mechanically, NF-κB signal elicited by macrophage inflammatory responses generated PD-L1+ cancer cells exhibiting capabilities to aggressively survive, support angiogenesis, and metastasize, whereas STAT1 signal triggered by activated T cells induced PD-L1+ cancer cells susceptive to apoptosis. Importantly, PD-L1+ cancer cells generated by macrophages established great resistance to conventional chemotherapy, cytotoxicity of tumor-specific effector T cells, and therapy of immune checkpoint blockade. Therapeutic strategy combining immune checkpoint blockade with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited caner regression. Our results provide insight into the functional features of PD-L1+ tumors and suggest that strategies to influence functional activities of inflammatory cells may benefit immune checkpoint blockade therapy.
- Subjects
CANCER cells; T cells; TREATMENT effectiveness; TUMORS; HETEROGENEITY
- Publication
Journal of Clinical Investigation, 2019, Vol 129, Issue 8, p3347
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI127726