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 5

PD-L1 signaling in myeloid cells harnesses antitumor immunity.

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PD-L1 signaling in myeloid cells harnesses antitumor immunity. (A) C57BL...
(A) C57BL/6 mice (n = 5) were inoculated with 1 × 106 WT MC38 cells and treated with 200 μg IgG or anti–PD-L1 on days 9 and 12. For cell depletion, 300 μg IgG, anti-CSF1R, or anti–Gr-1 Abs were injected from day 8. (B–D) C57BL/6 mice were reconstituted with mixed bone marrow cells from CD11b-DTR and PD-L1–/– mice. Eight weeks after reconstitution, mice were inoculated with 1 × 106 MC38 cells and treated with 200 μg anti–PD-L1 treatment on days 11 and 14 (n = 5). DT was injected intraperitoneally every other day from day 11. Twenty-four hours after the second DT injection, PD-L1 levels in tumor-infiltrating-CD11b+ cells were measured by flow cytometry (B). Tumor growth without (C) or with (D) DT was measured twice a week. (E and F) BMDMs from WT or PD-L1–/– mice were loaded with SIY peptide, then cocultured with 2C T cells for 3 days. (E) IFN-γ levels in culture supernatant were measured by CBA. (F) T cell activation was evaluated by flow cytometry. (G) DCs and CD8+ T cells were isolated from dLNs of MC38 tumor–bearing mice and cocultured for 4 days. Anti–PD-L1 or control IgG was added into medium at a concentration of 10 μg/ml. Cell culture supernatants were harvested, and IFN-γ levels were measured by CBA. Data indicate mean ± SEM and are representative of 2 (A, B, G) or 3 (E, F), or a pool of 2 (C, D) independent experiments. Statistical analysis was performed using an unpaired Student’s 2-tailed t test. *P < 0.05; **P < 0.01; ***P < 0.001.