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J Exp Med. 2017 Feb;214(2):381-400. doi: 10.1084/jem.20160485. Epub 2017 Jan 23.

The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment.

Author information

1
Departments of Pathology, Section of Hematology/Oncology, the University of Chicago, Chicago, IL 60637.
2
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
3
Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231.
4
Departments of Pathology, Section of Hematology/Oncology, the University of Chicago, Chicago, IL 60637 tgajewsk@medicine.bsd.uchicago.edu.
5
Department of Medicine, Section of Hematology/Oncology, the University of Chicago, Chicago, IL 60637.

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.

PMID:
28115575
PMCID:
PMC5294847
DOI:
10.1084/jem.20160485
[Indexed for MEDLINE]
Free PMC Article

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