Glucocorticoid-Induced TNF Receptor Family Related Gene Activation Overcomes Tolerance/Ignorance to Melanoma Differentiation Antigens and Enhances Antitumor Immunity

Hampton University, Hampton, Virginia, United States
The Journal of Immunology (Impact Factor: 4.92). 07/2006; 176(11):6434-42. DOI: 10.4049/jimmunol.176.11.6434
Source: PubMed


Glucocorticoid-induced TNF receptor family related protein (GITR) is present on many different cell types. Previous studies have shown that in vivo administration of an anti-GITR agonist mAb (DTA-1) inhibits regulatory T cells (Treg)-dependent suppression and enhances T cell responses. In this study, we show that administration of DTA-1 induces >85% tumor rejection in mice challenged with B16 melanoma. Rejection requires CD4+, CD8+, and NK1.1+ cells and is dependent on IFN-gamma and Fas ligand and independent of perforin. Depletion of Treg via anti-CD25 treatment does not induce B16 rejection, whereas 100% of the mice depleted of CD25+ cells and treated with DTA-1 reject tumors, indicating a predominant role of GITR on effector T cell costimulation rather than on Treg modulation. T cells isolated from DTA-1-treated mice challenged with B16 are specific against B16 and several melanoma differentiation Ags. These mice develop memory against B16, and a small proportion of them develop mild hypopigmentation. Consistent with previous studies showing that GITR stimulation increases Treg proliferation in vitro, we found in our model that GITR stimulation expanded the absolute number of FoxP3+ cells in vivo. Thus, we conclude that overall, GITR stimulation overcomes self-tolerance/ignorance and enhances T cell-mediated antitumor activity with minimal autoimmunity.

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    • "Extensive preclinical studies indicate that agonistic OX40 therapy can promote antitumor immunity by simultaneously expanding effector T cells while blocking Treg mediated suppression [75–80], particularly when delivered intratumourally [79]. Similarly agonistic 4-1BB therapy may enhance tumor immunity by enhancing effector function and protecting it from programmed cell death [81, 82], while anti-GITR therapy has been associated with the ability to break tolerance to melanoma differentiation antigens [83] and augment Treg accumulation within tumors [84]. Importantly, the antitumor potential of agonistic OX40, 4-1BB, and GITR immunotherapies can be significantly enhanced when combined with conventional cancer treatments such as chemotherapy, radiotherapy, surgery, or other immunotherapies [77, 85–87]. "
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    • "We also observed an increased percentage of splenic CD8+ T cells in combined mAb-treated mice compared with that in control or single mAb-treated mice (9.3 ± 3.1%, 10.3 ± 2.9%, 10.6 ± 3.0% or 13.1 ± 2.6% for control, anti-PD-1 or anti-OX40 or anti-PD-1/OX40 group); after normalization to the percentage of splenic CD8+ T cells, a significantly increased mesothelin-specific IFN-γ production from combined mAb-treated mice was still seen (data not shown). As an endogenous non-mutated antigen, mesothelin should be naturally tolerized against; therefore, the induction of mesothelin-specific CTL response by anti-PD-1/GITR mAb treatment indicates that endogenous tolerance to mesothelin was broken, which is consistent with previous studies demonstrating the overcome of tolerance/ignorance by GITR activation in murine tumors and the presence of mesothelin-specific immune response in patients with cancers expressing high level of mesothelin [24,35,36]. We did not detect mesothelin-specific antibodies in sera from mice treated with combined mAb (data not shown). "
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    Full-text · Article · Feb 2014 · Journal of Translational Medicine
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    • "Initially, it was assumed that GITR triggering on Tregs reduces their suppressive effect, but Stephens et al. showed that GITR expression is required on effector T cells but not on Tregs to alleviate Treg suppression [203]. More recent studies showed that the predominant effect of GITR triggering can be attributed to a potent costimulatory effect on effector T cells [204] [205]. Another recent study shows that GITR expression on CD8 + T cells is required for optimal responses against lethal influenza by enhancing the survival of CD8 + T cells [206]. "
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