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 D. 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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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