title: Exhaustion-associated regulatory regions in CD8+tumor-infiltrating T cells.
abstract: T-cell exhaustion is a progressive loss of effector function and memory potential due to persistent antigen exposure, which occurs in chronic viral infections and cancer. Here we investigate the relation between gene expression and chromatin accessibility in CD8+tumor-infiltrating lymphocytes (TILs) that recognize a model tumor antigen and have features of both activation and functional exhaustion. By filtering out accessible regions observed in bystander, nonexhausted TILs and in acutely restimulated CD8+T cells, we define a pattern of chromatin accessibility specific for T-cell exhaustion, characterized by enrichment for consensus binding motifs for Nr4a and NFAT transcription factors. Anti-PD-L1 treatment of tumor-bearing mice results in cessation of tumor growth and partial rescue of cytokine production by the dysfunctional TILs, with only limited changes in gene expression and chromatin accessibility. Our studies provide a valuable resource for the molecular understanding of T-cell exhaustion in cancer and other inflammatory settings.
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute, La Jolla, CA 92037.
authors.forename: Giuliana P
authors.initials: GP
authors.lastname: Mognol
authors.affiliation: Signaling Systems Laboratory, University of California, Los Angeles, CA 90095.
authors.forename: Roberto
authors.identifier: 0000-0001-8282-7658
authors.initials: R
authors.lastname: Spreafico
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute, La Jolla, CA 92037.
authors.forename: Victor
authors.initials: V
authors.lastname: Wong
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute, La Jolla, CA 92037.
authors.forename: James P
authors.initials: JP
authors.lastname: Scott-Browne
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute, La Jolla, CA 92037.
authors.forename: Susan
authors.initials: S
authors.lastname: Togher
authors.affiliation: Signaling Systems Laboratory, University of California, Los Angeles, CA 90095.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute, La Jolla, CA 92037.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Hogan
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute, La Jolla, CA 92037; arao@lji.org.|Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92037.|Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute, La Jolla, CA 92037.
authors.forename: Sara
authors.initials: S
authors.lastname: Trifari
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002843:Chromatin / Q000276:immunology; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics / Q000276:immunology*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000276:immunology; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D000951:Antigens, Neoplasm; D002843:Chromatin; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1
keywords: ATAC-seq; T-cell exhaustion; anti–PD-L1; checkpoint blockade therapy; chromatin accessibility