Dual Roles for Regulatory T-cell Depletion and Costimulatory Signaling in Agonistic GITR Targeting for Tumor Immunotherapy.
| Autor: | Mahne AE; Merck Research Laboratories, Palo Alto, California., Mauze S; Merck Research Laboratories, Palo Alto, California., Joyce-Shaikh B; Merck Research Laboratories, Palo Alto, California., Xia J; Merck Research Laboratories, Palo Alto, California., Bowman EP; Merck Research Laboratories, Palo Alto, California., Beebe AM; Merck Research Laboratories, Palo Alto, California., Cua DJ; Merck Research Laboratories, Palo Alto, California., Jain R; Merck Research Laboratories, Palo Alto, California. renujain429@gmail.com. |
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| Jazyk: | angličtina |
| Zdroj: | Cancer research [Cancer Res] 2017 Mar 01; Vol. 77 (5), pp. 1108-1118. Date of Electronic Publication: 2016 Oct 20. |
| DOI: | 10.1158/0008-5472.CAN-16-0797 |
| Abstrakt: | 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 CD44 hi ICOS hi intratumoral 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 . (©2016 American Association for Cancer Research.) |
| Databáze: | MEDLINE |
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