title: The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment.
abstract: Although the presence of tumor-infiltrating lymphocytes (TILs) indicates an endogenous antitumor response, immune regulatory pathways can subvert the effector phase and enable tumor escape. Negative regulatory pathways include extrinsic suppression mechanisms, but also a T cell-intrinsic dysfunctional state. A more detailed study has been hampered by a lack of cell surface markers defining tumor-specific dysfunctional TILs, and PD-1 alone is not sufficient. Recently, we identified the transcription factor Egr2 as a critical component in controlling the anergic state in vitro. In this study, we show that the Egr2-driven cell surface proteins LAG-3 and 4-1BB can identify dysfunctional tumor antigen-specific CD8+TIL. Co-expression of 4-1BB and LAG-3 was seen on a majority of CD8+TILs, but not in lymphoid organs. Functional analysis revealed defective IL-2 and TNF production yet retained expression of IFN-γ and regulatory T cell-recruiting chemokines. Transcriptional and phenotypic characterization revealed coexpression of multiple additional co-stimulatory and co-inhibitory receptors. Administration of anti-LAG-3 plus anti-4-1BB mAbs was therapeutic against tumors in vivo, which correlated with phenotypic normalization. Our results indicate that coexpression of LAG-3 and 4-1BB characterize dysfunctional T cells within tumors, and that targeting these receptors has therapeutic utility.
authors.affiliation: Departments of Pathology, Section of Hematology/Oncology, the University of Chicago, Chicago, IL 60637.
authors.forename: Jason B
authors.identifier: 0000-0002-8386-6285
authors.initials: JB
authors.lastname: Williams
authors.affiliation: Departments of Pathology, Section of Hematology/Oncology, the University of Chicago, Chicago, IL 60637.
authors.forename: Brendan L
authors.initials: BL
authors.lastname: Horton
authors.affiliation: Departments of Pathology, Section of Hematology/Oncology, the University of Chicago, Chicago, IL 60637.
authors.forename: Yan
authors.identifier: 0000-0001-9426-4127
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
authors.forename: Yukan
authors.identifier: 0000-0001-9614-8402
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Powell
authors.affiliation: Departments of Pathology, Section of Hematology/Oncology, the University of Chicago, Chicago, IL 60637 tgajewsk@medicine.bsd.uchicago.edu.|Department of Medicine, Section of Hematology/Oncology, the University of Chicago, Chicago, IL 60637.
authors.forename: Thomas F
authors.identifier: 0000-0001-5727-3972
authors.initials: TF
authors.lastname: Gajewski
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000502:physiology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D051767:Early Growth Response Protein 2 / Q000502:physiology*; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D059016:Tumor Microenvironment; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D007376:Interleukin-2; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma; D000068876:Fingolimod Hydrochloride; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse