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

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          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. Additionally, the capacity of PD-L1 to suppresses antitumor responses was inversely proportional to tumor cell antigenicity. PD-L1 expression on host cells, particularly tumor-associated macrophages (TAMs), was also important for tumor immune escape. We demonstrated that induction of PD-L1 on tumor cells was interferon gamma (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 to monitoring PD-L1 expression on tumor cells alone.

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          Author and article information

          Journal
          101614637
          41946
          Cancer Immunol Res
          Cancer Immunol Res
          Cancer immunology research
          2326-6066
          2326-6074
          5 May 2017
          10 January 2017
          February 2017
          01 February 2018
          : 5
          : 2
          : 106-117
          Affiliations
          [1 ]Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA
          [2 ]Department of Medicine, Division of Oncology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA
          [3 ]McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St. Louis, Missouri 63108, USA
          [4 ]Bristol-Myers Squibb, 740 Bay Road, Redwood City, CA 94063, USA
          [5 ]Bristol-Myers Squibb, Route 206 and Province Line Road, Lawrenceville, NJ 08540 USA
          [6 ]Department of Genetics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA
          [7 ]Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA
          Author notes
          [* ]Corresponding author: Address correspondence to Professor Robert D. Schreiber, Department of Pathology and Immunology, Washington University in St. Louis, 660 South Euclid Avenue, Box 8118, St. Louis, MO 63110, USA. rdschreiber@ 123456wustl.edu , phone: +1-314-362-8787
          Article
          PMC5510474 PMC5510474 5510474 nihpa843518
          10.1158/2326-6066.CIR-16-0391
          5510474
          28073774
          39479444-3e04-4d78-a39d-0209ffdc1946
          History
          Categories
          Article

          neoantigens,PD-L1,PD-1,cancer immunoediting,biomarker
          neoantigens, PD-L1, PD-1, cancer immunoediting, biomarker

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