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

Jason B. Williams, Brendan L. Horton, Yan Zheng, Yukan Duan, Jonathan Powell, Thomas F. Gajewski

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)381-400
Number of pages20
JournalJournal of Experimental Medicine
Volume214
Issue number2
DOIs
StatePublished - 2017

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CD8 Antigens
Tumor-Infiltrating Lymphocytes
Tumor Microenvironment
T-Lymphocytes
Tumor Escape
Neoplasm Antigens
Regulatory T-Lymphocytes
Tumor Biomarkers
Chemokines
Interleukin-2
Neoplasms
Membrane Proteins
Transcription Factors
Therapeutics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment. / Williams, Jason B.; Horton, Brendan L.; Zheng, Yan; Duan, Yukan; Powell, Jonathan; Gajewski, Thomas F.

In: Journal of Experimental Medicine, Vol. 214, No. 2, 2017, p. 381-400.

Research output: Contribution to journalArticle

Williams, Jason B. ; Horton, Brendan L. ; Zheng, Yan ; Duan, Yukan ; Powell, Jonathan ; Gajewski, Thomas F. / The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment. In: Journal of Experimental Medicine. 2017 ; Vol. 214, No. 2. pp. 381-400.
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