title: PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors.
abstract: Purpose:With recent approval of inhibitors of PD-1 in melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma, extensive efforts are under way to develop biomarkers predictive of response. PD-L1 expression has been most widely studied, and is more predictive in NSCLC than renal cell carcinoma or melanoma. We therefore studied differences in expression patterns across tumor types.Experimental Design:We used tissue microarrays with tumors from NSCLC, renal cell carcinoma, or melanoma and a panel of cell lines to study differences between tumor types. Predictive studies were conducted on samples from 65 melanoma patients treated with PD-1 inhibitors alone or with CTLA-4 inhibitors, characterized for outcome. PD-L1 expression was studied by quantitative immunofluorescence using two well-validated antibodies.Results:PD-L1 expression was higher in NSCLC specimens than renal cell carcinoma, and lowest in melanoma (P= 0.001), and this finding was confirmed in a panel of cell lines. In melanoma tumors, PD-L1 was expressed either on tumor cells or immune-infiltrating cells. The association between PD-L1 expression in immune-infiltrating cells and progression-free or overall-survival in melanoma patients treated with ipilimumab and nivolumab was stronger than PD-L1 expression in tumor cells, and remained significant on multivariable analysis.Conclusions:PD-L1 expression in melanoma tumor cells is lower than NSCLC or renal cell carcinoma cells. The higher response rate in melanoma patients treated with PD-1 inhibitors is likely related to PD-L1 in tumor-associated inflammatory cells. Further studies are warranted to validate the predictive role of inflammatory cell PD-L1 expression in melanoma and determine its biological significance.Clin Cancer Res; 23(15); 4270-9. ©2017 AACR.
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut. harriet.kluger@yale.edu.
authors.forename: Harriet M
authors.initials: HM
authors.lastname: Kluger
authors.affiliation: Department of Biology, School of Health and Natural Sciences, University of Saint Joseph, West Hartford, Connecticut.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Zito
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.|Department of Dermatology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Turcu
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Marina K
authors.initials: MK
authors.lastname: Baine
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adeniran
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Kluger
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Justine V
authors.initials: JV
authors.lastname: Cohen
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Lucia B
authors.initials: LB
authors.lastname: Jilaveanu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D046888:Tissue Array Analysis
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab