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J Clin Invest. 2018 Feb 1;128(2):805-815. doi: 10.1172/JCI96113. Epub 2018 Jan 16.

Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression.

Author information

1
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
2
Oncology Research, MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland, USA.
3
Department of Radiation Oncology.
4
Department of Biostatistics.
5
Department of Pathology.
6
Department of Dermatology, and.
7
Department of Medicine.
8
Michigan Center for Translational Pathology.
9
Howard Hughes Medical Institute, and.
10
University of Michigan Comprehensive Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
11
Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
12
Graduate Programs in Immunology and Cancer Biology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

Abstract

Programmed death-1 receptor (PD-L1, B7-H1) and programmed cell death protein 1 (PD-1) pathway blockade is a promising therapy for treating cancer. However, the mechanistic contribution of host and tumor PD-L1 and PD-1 signaling to the therapeutic efficacy of PD-L1 and PD-1 blockade remains elusive. Here, we evaluated 3 tumor-bearing mouse models that differ in their sensitivity to PD-L1 blockade and demonstrated a loss of therapeutic efficacy of PD-L1 blockade in immunodeficient mice and in PD-L1- and PD-1-deficient mice. In contrast, neither knockout nor overexpression of PD-L1 in tumor cells had an effect on PD-L1 blockade efficacy. Human and murine studies showed high levels of functional PD-L1 expression in dendritic cells and macrophages in the tumor microenvironments and draining lymph nodes. Additionally, expression of PD-L1 on dendritic cells and macrophages in ovarian cancer and melanoma patients correlated with the efficacy of treatment with either anti-PD-1 alone or in combination with anti-CTLA-4. Thus, PD-L1-expressing dendritic cells and macrophages may mechanistically shape and therapeutically predict clinical efficacy of PD-L1/PD-1 blockade.

KEYWORDS:

Cancer immunotherapy; Immunology

PMID:
29337305
PMCID:
PMC5785251
DOI:
10.1172/JCI96113
[Indexed for MEDLINE]
Free PMC Article

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