The local immune landscape determines tumor PD-L1 heterogeneity and sensitivity to therapy
Yuan Wei, … , Limin Zheng, Dong-Ming Kuang
Yuan Wei, … , Limin Zheng, Dong-Ming Kuang
Published May 21, 2019
Citation Information: J Clin Invest. 2019;129(8):3347-3360. https://doi.org/10.1172/JCI127726.
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Research Article Immunology Inflammation Article has an altmetric score of 13

The local immune landscape determines tumor PD-L1 heterogeneity and sensitivity to therapy

Abstract

Programmed death-1 receptor ligand 1 (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 showed, in detailed studies of gene data regarding 9769 patients of 32 types of human cancers, that PD-L1 could not exclusively represent the IFN-γ signature and potentially signified proinflammatory 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 cancer 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.

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

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Figure 7

PD-L1+ tumors generated differently respond to therapeutic strategies distinctly.

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PD-L1+ tumors generated differently respond to therapeutic strategies di...
(A) PD-L1+ HepG2 cells were generated by transducing with pBABE-Puro retroviral vector encoding human CD274 or incubating with tumor T cell–CM or TAM-CM. Survival of cells after 48-hour exposure to doxorubicin was determined (n = 4). (B and C) Incubating with an inhibitor against NF-κB (B) and knockdown of P65 NF-κB subunit (siRELA, C) in HepG2 cells attenuated TAM-CM–mediated resistance to doxorubicin (0.25 μg/mL; n = 7 for B and n = 6 for C). (D–G) PD-L1+ hepatoma Hepa1-6 cells were generated by transducing with pBABE-Puro retroviral vector encoding mouse CD274 or by exposure to CM from Hepa1-6 hepatoma–derived macrophages or T cells (D). Thereafter, these cells were left untreated or cultured with Hepa1-6 hepatoma–derived CD8+ T cells in the presence of control IgG or an Ab against PD-L1. Survival of Hepa1-6 cells at indicated times (E), 24-hour production of IFN-γ and IL-2 by T cells (F), and 24-hour expression or CD107a on T cells (G) were determined. Data represent mean ± SEM. Results are representative of at least 4 separate experiments. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA with Dunett’s post test (A, F, and G), Student’s t test (B and C), or 2-way ANOVA with Bonferroni’s post test (E).