PD-L1 on host cells is essential for PD-L1 blockade–mediated tumor regression
Haidong Tang, … , Hua Peng, Yang-Xin Fu
Haidong Tang, … , Hua Peng, Yang-Xin Fu
Published January 16, 2018
Citation Information: J Clin Invest. 2018;128(2):580-588. https://doi.org/10.1172/JCI96061.
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Research Article Immunology Oncology Article has an altmetric score of 83

PD-L1 on host cells is essential for PD-L1 blockade–mediated tumor regression

Abstract

Programmed death–ligand 1 (PD-L1) expression on tumor cells is essential for T cell impairment, and PD-L1 blockade therapy has shown unprecedented durable responses in several clinical studies. Although higher expression of PD-L1 on tumor cells is associated with a better immune response after Ab blockade, some PD-L1–negative patients also respond to this therapy. In the current study, we explored whether PD-L1 on tumor or host cells was essential for anti–PD-L1–mediated therapy in 2 different murine tumor models. Using real-time imaging in whole tumor tissues, we found that anti–PD-L1 Ab accumulates in tumor tissues, regardless of the status of PD-L1 expression on tumor cells. We further observed that, while PD-L1 on tumor cells was largely dispensable for the response to checkpoint blockade, PD-L1 in host myeloid cells was essential for this response. Additionally, PD-L1 signaling in defined antigen-presenting cells (APCs) negatively regulated and inhibited T cell activation. PD-L1 blockade inside tumors was not sufficient to mediate regression, as limiting T cell trafficking reduced the efficacy of the blockade. Together, these findings demonstrate that PD-L1 expressed in APCs, rather than on tumor cells, plays an essential role in checkpoint blockade therapy, providing an insight into the mechanisms of this therapy.

Authors

Haidong Tang, Yong Liang, Robert A. Anders, Janis M. Taube, Xiangyan Qiu, Aditi Mulgaonkar, Xin Liu, Susan M. Harrington, Jingya Guo, Yangchun Xin, Yahong Xiong, Kien Nham, William Silvers, Guiyang Hao, Xiankai Sun, Mingyi Chen, Raquibul Hannan, Jian Qiao, Haidong Dong, Hua Peng, Yang-Xin Fu

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Figure 3

Preexisting TIL is insufficient for the effects of PD-L1 blockade.

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Preexisting TIL is insufficient for the effects of PD-L1 blockade. (A) B...
(A) B6.Rag–/– mice (n = 5) were inoculated with 1 × 106 MC38 cells. After tumors were established, mice were treated with 200 μg anti–PD-L1 on days 8 and 11. Tumor growth was measured twice a week. (B) C57BL/6 mice (n = 5) were inoculated with 1 × 106 MC38 cells. Mice were treated with 200 μg anti–PD-L1 on days 8 and 11. For CD8+ T cell depletion, mice were treated with 200 μg anti-CD8 on days 8, 11, and 14. (C–E) MC38 tumor–bearing mice (n = 5 per group) were treated with 200 μg IgG or anti–PD-L1 on days 8 and 11. Mice were also treated with control (C) or FTY720 from day 0 (D) or day 8 (E). (F) MC38 tumor-bearing mice were treated with IgG or anti–PD-L1 (n = 3 per group). Two days later, dLN were isolated and single-cell suspensions were prepared. Cells were cocultured with or without MC38 cells for 2 days. IFN-γ+ cells were measured by ELISPOT. (G) MC38 tumor–bearing mice were treated with anti–PD-L1 and FTY720 as in C–E. Three days after anti–PD-L1 treatment, dLNs were isolated. ELISPOT assay was performed. Data indicate mean ± SEM and are representative of 2 independent experiments. Statistical analysis was performed using an unpaired Student’s 2-tailed t test. *P < 0.05; **P < 0.01; ***P < 0.001. ND, not detectable.