title: Temporally Distinct PD-L1 Expression by Tumor and Host Cells Contributes to Immune Escape.
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. ©2017 AACR.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Takuro
authors.initials: T
authors.lastname: Noguchi
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.|Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Ward
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Gubin
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Cora D
authors.initials: CD
authors.lastname: Arthur
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Sang Hun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jasreet
authors.initials: J
authors.lastname: Hundal
authors.affiliation: Bristol-Myers Squibb, Redwood City, California.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Selby
authors.affiliation: Bristol-Myers Squibb, Lawrenceville, New Jersey.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Graziano
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.|Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: Bristol-Myers Squibb, Redwood City, California.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Korman
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri. rdschreiber@wustl.edu.|Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D055786:Gene Knockout Techniques; D005805:Genes, MHC Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D012509:Sarcoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D047368:Tumor Burden; D019139:Tumor Escape / Q000235:genetics* / Q000276:immunology*; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen