title: Eomesodermin is required for antitumor immunity mediated by 4-1BB-agonist immunotherapy.
abstract: CD8+T cells in progressing tumors frequently fail to mount an effective antitumor response often in association with the expression of inhibitory receptors, including programmed cell death-1 (PD-1) and lymphocyte-activation gene 3 (Lag3). Using a lymphoma tumor model, we demonstrate that tumor-infiltrating CD8+T cells from growing tumors co-express inhibitory receptors and co-stimulatory receptors, including 4-1BB (TNFRSF9) as well as high levels of 2 transcription factors, Eomesodermin (Eomes) and T-bet (Tbx21), critical determinants of CD8+T cell fate. Immunotherapy with an agonistic anti-4-1-BB antibody altered the ratio of Eomes to T-bet expression in tumor-infiltrating CD8+T cells by increasing Eomes and decreasing T-bet expression. 4-1BB-agonist immunotherapy was also associated with downregulated expression of the inhibitory receptors PD-1 and Lag3 on tumor-infiltrating CD8+T cells, a molecular phenotype associated with subsequent attenuation of tumor growth. Furthermore, 4-1BB-agonist immunotherapy failed to effect tumor progression in mice with Eomes deficient T cells. However, upon resumption of tumor growth, tumor-infiltrating CD8+T cells from treated animals continued to express high levels of Eomes as well as elevated levels of the inhibitory receptors PD-1 and Lag3. Our data suggest that tumor-infiltrating CD8+T cells are poised between activation and inhibition as dictated by expression of both co-stimulatory receptors and inhibitory receptors and demonstrate that T cell expression of Eomes is necessary, but not sufficient, for efficacious 4-1BB-agonist-mediated immunotherapy.
authors.affiliation: Program in Oncology; Greenebaum Cancer Center; Center for Stem Cell Research and Regenerative Medicine; Department of Medicine; University of Maryland School of Medicine; Baltimore, MD USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Song
authors.affiliation: Program in Oncology; Greenebaum Cancer Center; Center for Stem Cell Research and Regenerative Medicine; Department of Medicine; University of Maryland School of Medicine; Baltimore, MD USA.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Sadashivaiah
authors.affiliation: Program in Oncology; Greenebaum Cancer Center; Center for Stem Cell Research and Regenerative Medicine; Department of Medicine; University of Maryland School of Medicine; Baltimore, MD USA.
authors.forename: Aki
authors.initials: A
authors.lastname: Furusawa
authors.affiliation: Department of Otolaryngology; University of Maryland School of Medicine; Baltimore, MD USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Davila
authors.affiliation: Department of Immunology and Cellular Signal Analysis; Yamaguchi University School of Medicine; Ube, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tamada
authors.affiliation: Program in Oncology; Greenebaum Cancer Center; Center for Stem Cell Research and Regenerative Medicine; Department of Medicine; University of Maryland School of Medicine; Baltimore, MD USA.
authors.forename: Arnob
authors.initials: A
authors.lastname: Banerjee
keywords: 4-1BB; Lag3; PD-1; T cells; eomesodermin; tumor immunotherapy