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 February 1, 2018
Citation Information: J Clin Invest. 2018;128(2):580-588. https://doi.org/10.1172/JCI96061.
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Categories: Research Article Immunology Oncology

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 1

Tumor-expressed PD-L1 is dispensable for responses to checkpoint blockade therapy.

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Tumor-expressed PD-L1 is dispensable for responses to checkpoint blockad...
(A) C57BL/6 mice were inoculated with 1 × 106 MC38 cells. Spleen, dLN, and tumor tissues were collected on day 22. PD-L1 expression was measured by flow cytometry. FMO, fluorescence minus one. (B–D) Mean fluorescent intensities (MFIs) of PD-L1 staining in spleen (B), dLN (C), and tumor (D) are shown (n = 3 per group). (E) PD-L1 expression in MC38.WT, MC38.PD-L1–/–, A20.WT, and A20.PD-L1–/– cells was measured by flow cytometry. To induce PD-L1 expression, cells were treated with 500 U/ml IFN-γ for 24 hours. (F and G) C57BL/6 mice (n = 5 or 6) were inoculated with 1 × 106 MC38.WT or MC38.PD-L1–/– cells. After tumors were established, mice were treated with 200 μg anti–PD-L1 on days 7, 10, and 13. Tumor growth (F) and survival curve (G) are shown. (H and I) BALB/c mice (n = 5) were inoculated with 3 × 106 A20.WT or A20.PD-L1–/– cells. Mice were treated with 200 μg anti–PD-L1 on days 10 and 13. Tumor growth (H) and survival curve (I) are shown. (J–L) Tissues were collected from MC38.PD-L1–/– tumor-bearing mice. Mean fluorescent intensities of PD-L1 staining in spleen (J), dLN (K), and tumor (L) are shown (n = 3). Data indicate mean ± SEM and are representative of at least 2 independent experiments. Statistical analysis was performed using an unpaired Student’s 2-tailed t test.