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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.

Author information

1
Department of Pathology, University of Texas (UT) Southwestern Medical Center, Dallas, Texas, USA.
2
Chinese Academy of Sciences Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
3
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4
Department of Dermatopathology and the Bloomberg-Kimmel Institute of Cancer Immunotherapy and.
5
Department of Radiology, UT Southwestern Medical Center, Dallas, Texas, USA.
6
Departments of Urology and Immunology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
7
Department of Applied Chemistry, College of Materials and Energy, South China Agricultural University, Guangzhou, Guangdong, China.
8
Department of Radiology and Advanced Imaging Research Center and.
9
Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas, USA.

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.

KEYWORDS:

Cancer immunotherapy; Cellular immune response; Immunology; Oncology

PMID:
29337303
PMCID:
PMC5785245
DOI:
10.1172/JCI96061
[Indexed for MEDLINE]
Free PMC Article

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