Todd Bartkowiak1,2, Ashvin R. Jaiswal, Midan Ai1, Pratha Budhani1, Casey Ager1,2, Courtney Nicholas1, Renee Chin1, Chao-Hsien Chen1,2, and Michael A. Curran1,2
1University of Texas MD Anderson Cancer Center, Department of Immunology, Houston TX 77054
2University of Texas Graduate School of Biomedical Science at Houston, Program in Immunology, Houston TX 77054
Targeting immune inhibitory (CTLA-4, PD-1) or stimulatory (OX-40, 4-1BB) co-receptors has proven to be a potent anti-cancer therapeutic strategy, eliciting robust anti-tumor T cell responses and yielding compelling pre-clinical and clinical data in a variety of cancers. We have previously shown in pre-clinical models that 4-1BB agonist antibodies engender strong anti-tumor T cell responses capable of driving regression of established tumors and durable tumor-free survival. This impressive anti-tumor effect is due, in part, to the unique ability of 4-1BB co-stimulation to differentiate a novel subset of T cells that acquires a highly cytotoxic effector profile typically only seen in NK cells. This phenotype, known as ThEO (CD4+) or TcEO (CD8+), is driven by the T-box transcription factor Eomesodermin, and is further characterized by expression of the inhibitory receptor KLRG1. We show here that, despite high level effector function and expression of several co-inhibitory receptors (PD-1, TIM-3, KLRG1), these ThEO/TcEO phenotype T cells efficiently establish immunologic memory and recall with high frequency upon secondary tumor challenge. Further, they maintain high effector function on recall and can traffic to tissue sites far removed from the original malignancy. These findings provide mechanistic insight into the ability of 4-1BB agonist antibodies to generate potent anti-tumor responses, as well as processes that mediate memory formation and give evidence for the capacity of ThEO/TcEO cells to prevent tumor recurrence.
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