title: Dual Roles for Regulatory T-cell Depletion and Costimulatory Signaling in Agonistic GITR Targeting for Tumor Immunotherapy.
abstract: Agonistic monoclonal antibodies (mAb) targeting the T-cell receptor coregulatory molecule GITR exert potent therapeutic activities in preclinical tumor models. Although anti-GITR mAb are thought to act by depleting and destabilizing the intratumoral T regulatory cell (Treg) population, the precise mechanism of action is obscure. Here, we addressed this issue using a Treg fate-mapping approach, which revealed that Treg loss was primarily due to cell depletion, with minimal evidence of Treg conversion to a non-Foxp3-expressing population. Further characterization of persisting Tregs following anti-GITR mAb treatment showed that a highly activated subpopulation of CD44hiICOShiintratumoral Tregs were preferentially targeted for elimination, with the remaining Tregs exhibiting a less suppressive phenotype. With these changes in the Treg population, intratumoral CD8+T cells acquired a more functional phenotype characterized by downregulation of the exhaustion markers PD-1 and LAG-3. This reversal of CD8+T-cell exhaustion was dependent on both agonistic GITR signaling and Treg depletion, as neither mechanism by itself could fully rescue the exhaustion phenotype. Tests of anti-human GITR antibody MK-4166 in a humanized mouse model of cancer mimicked many of the effects of anti-mouse GITR mAb in syngeneic tumor models, decreasing both Treg numbers and immune suppressor phenotype while enhancing effector responsiveness. Overall, our results show how anti-GITR mAb shifts Treg populations to enable immune attack on tumors, with clinical implications for molecular markers to modify emerging treatments.Cancer Res; 77(5); 1108-18. ©2016 AACR.
authors.affiliation: Merck Research Laboratories, Palo Alto, California.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Mahne
authors.affiliation: Merck Research Laboratories, Palo Alto, California.
authors.forename: Smita
authors.initials: S
authors.lastname: Mauze
authors.affiliation: Merck Research Laboratories, Palo Alto, California.
authors.forename: Barbara
authors.initials: B
authors.lastname: Joyce-Shaikh
authors.affiliation: Merck Research Laboratories, Palo Alto, California.
authors.forename: Jane
authors.initials: J
authors.lastname: Xia
authors.affiliation: Merck Research Laboratories, Palo Alto, California.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Bowman
authors.affiliation: Merck Research Laboratories, Palo Alto, California.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Beebe
authors.affiliation: Merck Research Laboratories, Palo Alto, California.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cua
authors.affiliation: Merck Research Laboratories, Palo Alto, California. renujain429@gmail.com.
authors.forename: Renu
authors.initials: R
authors.lastname: Jain
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000819:agonists / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008212:Lymphocyte Depletion / Q000379:methods*; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D053450:Glucocorticoid-Induced TNFR-Related Protein