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

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 8

Suppressing macrophage-elicited NF-κB activation augments immunotherapeutic efficacy of a PD-L1 Ab.

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Suppressing macrophage-elicited NF-κB activation augments immunotherapeu...
(A and B) Mice bearing Hepa1-6 hepatoma in dorsal tissues for 15 days were left untreated or were treated with isotype, αCSF1R Ab, αPD-L1 Ab, or αCSF1R Ab plus αPD-L1 Ab as described (A). Tumor sizes over the indicated time were analyzed (B, n = 8). (C and D) WT (untreated or shNC) or P65 knockdown (shRELA) Hepa1-6 cells were inoculated in dorsal tissues of C57BL/6 mice. Thereafter, mice bearing P65 knockdown (shRELA) Hepa1-6 hepatoma were untreated or treated with isotype or αPD-L1 Ab (C). Tumor sizes over the indicated time were analyzed (D, n = 8). (E) Correlation between CD68 expression and the scoring of the NF-κB pathway were calculated in HCC, STAD, COAD, and LUAD patients from the TCGA data set. (F) Statistical analysis was conducted based on the scoring of the NF-κB pathway and recurrence rate in HCC, STAD, COAD, and LUAD patients from the TCGA data set. P values and R values were calculated based on the analysis of Pearson’s correlation. Data represent mean ± SEM. Results are representative of 3 separate experiments. ***P < 0.001, 1-way ANOVA with Bonferroni’s post test (B and D) or χ2 test (F).