Data from GITR Pathway Activation Abrogates Tumor Immune Suppression through Loss of Regulatory T-cell Lineage Stability

• DOI: 10.1158/2326-6066.c.6547961
• Publication Date: 2024-03-12T20:00:52Z
• Authors: David A. Schaer; Sadna Budhu; Cailian Liu; Campbell Bryson; Nicole Malandro; Adam Cohen; Hong Zhong; Xia Yang; Alan N. Houghton; Taha Merghoub; Jedd D. Wolchok
• Keywords: Regulatory T cell; Lineage (genetic)

<div>Abstract<p>Ligation of GITR (glucocorticoid-induced TNF receptor-related gene, or TNFRSF18) by agonist antibody has recently entered into early-phase clinical trials for the treatment advanced malignancies. Although ability modulation to induce tumor regression is well documented in preclinical studies, underlying mechanisms action, particularly its effects on CD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells (Treg), have not been fully elucidated. We previously shown that ligation <i>in vivo</i> DTA-1 causes more than 50% reduction intratumor Tregs with down Foxp3 expression. Here, we show loss dependent. Adoptively transferred Foxp3<sup>+</sup> from tumor-bearing animals lose expression host when treated DTA-1, whereas naïve mice maintain also alters various transcription factors and cytokines important Treg function. Complete correlates a dramatic decrease Helios associated upregulation factors, T-Bet Eomes. Changes correspond interleukin (IL)-10 an increase IFN-γ DTA-1–treated Tregs. Together, these data lineage stability inducing inflammatory effector T-cell phenotype. The resultant their immune-suppressive function, making susceptible killing tumor-specific CD8<sup>+</sup> cells. <i>Cancer Immunol Res; 1(5); 320–31. ©2013 AACR</i>.</p></div>