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Gene expression of dysfunctional CD8+ T cells from the tumor microenvironment

ABSTRACT: Although the presence of tumor-infiltrating lymphocytes (TILs) indicates an endogenous anti-tumor 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 dysfunctional TILs, and it is clear that 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 the current study we show that the Egr2-driven cell surface proteins, LAG-3 and 4-1BB, identify dysfunctional tumor antigen-specific CD8+ TIL. Co-expression of 4-1BB and LAG-3 was seen on a majority of CD8+ TIL but not in lymphoid organs. Functional analysis revealed defective IL-2 and TNF-α production yet retained expression of IFN-γ and Treg-recruiting chemokines. Transcriptional and phenotypic characterization revealed co-expression 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 a reversal of TIL dysfunction and restored effector phenotype. Our results indicate that co-expression of LAG-3 and 4-1BB characterize dysfunctional T cells within tumors, and that targeting these receptors has therapeutic utility.

ORGANISM(S): Mus musculus

PROVIDER: GSE79919 | GEO | 2016/04/05

SECONDARY ACCESSION(S): PRJNA317374

REPOSITORIES: GEO

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