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Cancer Immunol Res. 2017 Feb;5(2):106-117. doi: 10.1158/2326-6066.CIR-16-0391. Epub 2017 Jan 10.

Temporally Distinct PD-L1 Expression by Tumor and Host Cells Contributes to Immune Escape.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
2
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
3
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
4
Bristol-Myers Squibb, Redwood City, California.
5
Bristol-Myers Squibb, Lawrenceville, New Jersey.
6
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
7
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri. rdschreiber@wustl.edu.
8
Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, Missouri.

Abstract

Antibody blockade of programmed death-1 (PD-1) or its ligand, PD-L1, has led to unprecedented therapeutic responses in certain tumor-bearing individuals, but PD-L1 expression's prognostic value in stratifying cancer patients for such treatment remains unclear. Reports conflict on the significance of correlations between PD-L1 on tumor cells and positive clinical outcomes to PD-1/PD-L1 blockade. We investigated this issue using genomically related, clonal subsets from the same methylcholanthrene-induced sarcoma: a highly immunogenic subset that is spontaneously eliminated in vivo by adaptive immunity and a less immunogenic subset that forms tumors in immunocompetent mice, but is sensitive to PD-1/PD-L1 blockade therapy. Using CRISPR/Cas9-induced loss-of-function approaches and overexpression gain-of-function techniques, we confirmed that PD-L1 on tumor cells is key to promoting tumor escape. In addition, the capacity of PD-L1 to suppress antitumor responses was inversely proportional to tumor cell antigenicity. PD-L1 expression on host cells, particularly tumor-associated macrophages (TAM), was also important for tumor immune escape. We demonstrated that induction of PD-L1 on tumor cells was IFNγ-dependent and transient, but PD-L1 induction on TAMs was of greater magnitude, only partially IFNγ dependent, and was stable over time. Thus, PD-L1 expression on either tumor cells or host immune cells could lead to tumor escape from immune control, indicating that total PD-L1 expression in the immediate tumor microenvironment may represent a more accurate biomarker for predicting response to PD-1/PD-L1 blockade therapy, compared with monitoring PD-L1 expression on tumor cells alone. Cancer Immunol Res; 5(2); 106-17.

PMID:
28073774
PMCID:
PMC5510474
DOI:
10.1158/2326-6066.CIR-16-0391
[Indexed for MEDLINE]
Free PMC Article

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