دورية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment
المؤلفون: Williams, Jason B., Horton, Brendan L., Zheng, Yan, Duan, Yukan, Powell, Jonathan D., Gajewski, Thomas F.
المصدر: The Journal of Experimental Medicine; February 2017, Vol. 214 Issue: 2 p381-400, 20p
مستخلص: 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.
قاعدة البيانات: Supplemental Index
الوصف
تدمد:00221007
15409538
DOI:10.1084/jem.20160485