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J Clin Invest. 2018 Feb 1;128(2):580-588. doi: 10.1172/JCI96061. Epub 2018 Jan 16.

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

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Department of Pathology, University of Texas (UT) Southwestern Medical Center, Dallas, Texas, USA.
Chinese Academy of Sciences Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Dermatopathology and the Bloomberg-Kimmel Institute of Cancer Immunotherapy and.
Department of Radiology, UT Southwestern Medical Center, Dallas, Texas, USA.
Departments of Urology and Immunology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Department of Applied Chemistry, College of Materials and Energy, South China Agricultural University, Guangzhou, Guangdong, China.
Department of Radiology and Advanced Imaging Research Center and.
Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas, USA.


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.


Cancer immunotherapy; Cellular immune response; Immunology; Oncology

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