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

Department of Medicine and Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
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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    Research Journal of Immunology 05/2014; 2014. DOI:10.1155/2014/789069
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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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    ABSTRACT: The coinhibitory receptor Programmed Death-1 (PD-1) inhibits effector functions of activated T cells and prevents autoimmunity, however, cancer hijack this pathway to escape from immune attack. The costimulatory receptor glucocorticoid-induced TNFR related protein (GITR) is up-regulated on activated T cells and increases their proliferation, activation and cytokine production. We hypothesize that concomitant PD-1 blockade and GITR triggering would synergistically improve the effector functions of tumor-infiltrating T cells and increase the antitumor immunity. In present study, we evaluated the antitumor effects and mechanisms of combined PD-1 blockade and GITR triggering in a clinically highly relevant murine ID8 ovarian cancer model. Mice with 7 days-established peritoneal ID8 ovarian cancer were treated intraperitoneally (i.p.) with either control, anti-PD-1, anti-GITR or anti-PD-1/GITR monoclonal antibody (mAb) and their survival was evaluated; the phenotype and function of tumor-associated immune cells in peritoneal cavity of treated mice was analyzed by flow cytometry, and systemic antigen-specific immune response was evaluated by ELISA and cytotoxicity assay. Combined anti-PD-1/GITR mAb treatment remarkably inhibited peritoneal ID8 tumor growth with 20% of mice tumor free 90 days after tumor challenge while treatment with either anti-PD-1 or anti-GITR mAb alone exhibited little antitumor effect. The durable antitumor effect was associated with a memory immune response and conferred by CD4+ cells and CD8+ T cells. The treatment of anti-PD-1/GITR mAb increased the frequencies of interferon-gamma-producing effector T cells and decreased immunosuppressive regulatory T cells and myeloid-derived suppressor cells, shifting an immunosuppressive tumor milieu to an immunostimulatory state in peritoneal cavity. In addition, combined treatment of anti-PD-1/GITR mAb mounted an antigen-specific immune response as evidenced by antigen-specific IFN-gamma production and cytolytic activity of spleen cells from treated mice. More importantly, combined treatment of anti-PD-1/GITR mAb and chemotherapeutic drugs (cisplatin or paclitaxel) further increased the antitumor efficacy with 80% of mice obtaining tumor-free long-term survival in murine ID8 ovarian cancer and 4 T1 breast cancer models. Combined anti-PD-1/GITR mAb treatment induces a potent antitumor immunity, which can be further promoted by chemotherapeutic drugs. A combined strategy of anti-PD-1/GITR mAb plus cisplatin or paclitaxel should be considered translation into clinic.
    Journal of Translational Medicine 02/2014; 12(1):36. DOI:10.1186/1479-5876-12-36 · 3.93 Impact Factor
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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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    Current Molecular Medicine 03/2011; 11(3):172-96. DOI:10.2174/1566211213754945240 · 3.62 Impact Factor
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