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 2

Immune landscapes of PD-L1hi cancers affect patients’ clinical outcomes.

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Immune landscapes of PD-L1hi cancers affect patients’ clinical outcomes....
(A) Correlations between CD274 and indicated genes were calculated in 9138 patients with 32 types of cancer samples from TCGA data set. (B) Correlations of macrophage and T cell densities with PD-L1 expression in HCC tissues (n = 276). Student’s t test. (C) Confocal microscopy analysis of PD-L1+ cells (green), CD68+ macrophages (red), and CD3+ T cells (white) in HCC tissue. Results represent 3 independent experiments (n = 8). Scale bar: 100 μm. (D) Densities of macrophages and T cells in PD-L1lo or PD-L1hi COAD (n = 82), STAD (n = 78), and LUAD (n = 89) tissues. (E) 276 Patients with HCC were divided into 2 groups according to the median value of CD274 expression in tumors: red lines, low expression (n = 138); black lines, high expression (n = 138). 138 CD274hi patients were further divided into 4 groups according to the ratio of macrophages to T cells in tumors: orange line, ratio value > 2, n = 39; green line, ratio value ≤ 2 and > 1, n = 30; purple line, ratio value ≤ 1 and > 0.5, n = 31; blue line, ratio value ≤ 0.5, n = 38. (F and G) Univariate (F) and multivariate (G) regression analyses of factors associated with recurrence. Cox proportional hazards regression model. (H) 82, 78, and 89 Patients with COAD, STAD, and LUAD, respectively, were analyzed for the prognosis value of CD274 expression plus macrophage/T cell ratio. Patients were divided into 2 groups according to the value of CD274 expression in tumors or ratio of macrophages to T cells in CD274hi tumors. Recurrence times were calculated by the Kaplan-Meier method and analyzed by the log-rank test. ***P < 0.001.