Systemic 4-1BB activation induces a novel T-cell phenotype driven by high expression of Eomesodermin (P2197)

Abstract

Abstract Following treatment with 4-1BB agonist antibody, a novel population of KLRG1+ T-cells infiltrate the tumors of mice. Compared to their KLRG1- counterparts, these T-cells express high levels of cytotoxicity associated genes in both the CD4 and CD8 lineages and also demonstrate enhanced tumor-specific killing in vitro. The phenotype of these KLRG1+ cells is dependent on high expression of the T-box transcription factor Eomesodermin (Eomes). The unique ability of α4-1BB to generate this phenotype stems from the expression of 4-1BB by antigen presenting cells (APC) which respond to its activation by producing cytokines which then drive the development of these Eomes+KLRG1+ T-cells. By analyzing changes in APC cytokine production in vivo, as well as by using a series of gene knockout mice we have begun to identify the factors necessary to generate this novel T-cell lineage. Among these factors, IL-27, IL-15, and IL-10 appear to be paramount. These T-cells represent a novel polarity we have termed ThEO (CD4) and TcEO (CD8) which resolves multiple questions associated with 4-1BB activation including how 4-1BB enhances tumor-specific cytotoxicity, and how 4-1BB can promote tumor immunity while repressing autoimmunity. Understanding the nature of this novel lineage of highly tumoricidal T-cells in both tumor and pathogen-specific immunity may provide critical information for converting sub-optimal anti-tumor responses to therapeutically successful ones.