Modulation of GITR for cancer immunotherapy

Schaer, David; Murphy, Judith T.; Wolchok, Jedd D.

doi:10.1016/j.coi.2011.12.011

Cited by 129 publications

(119 citation statements)

References 68 publications

(103 reference statements)

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“…In this study, we demonstrate that GCsMs regulate activated CD8 Because GCsMs share the expression of CD11b, Gr-1, and CD124 (21) with monocytic MDSCs, which are known suppressors of T cell activation (30,37), and because genes involved in T cell interaction were overrepresented among GC-regulated genes, we wondered whether GCsMs would suppress T cell activation. We demonstrated that GCsMs suppress activation of CD8 + T cells in vitro, as was described for MDSCs (39,(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Immune Suppression via Glucocorticoid-Stimulated Monocytes: A Novel Mechanism To Cope with Inflammation

Varga

Ehrchen

Brockhausen

et al. 2014

The Journal of Immunology

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Glucocorticoids (GCs) are used as first-line therapies for generalized suppression of inflammation (e.g., allergies or autoimmune diseases), but their long-term use is limited by severe side effects. Our previous work revealed that GCs induced a stable anti-inflammatory phenotype in monocytes, the GC-stimulated monocytes (GCsMs) that we exploited for targeted GC-mediated therapeutic effects. We demonstrate that GCsMs interact with T cells in suppressing proliferation, as well as cytokine release of CD8+ and, especially, CD4+ T cells in vitro, and that they support generation of Foxp3+ cells. Therefore, we tested their immunosuppressive potential in CD4+ T cell–induced colitis in vivo. We found that injection of GCsMs into mice with severe colitis abolished the inflammation and resulted in significant clinical improvement within a few days. T cells recovered from GCsM-treated mice exhibited reduced secretion of proinflammatory cytokines IFN-γ and IL-17. Furthermore, clusters of Foxp3+ CD4+ T cells were detectable at local sites of inflammation in the colon. Thus, GCsMs are able to modify T cell responses in vitro and in vivo, as well as to downregulate and clinically cure severe T cell–mediated colitis.

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Section: Discussionmentioning

confidence: 99%

Immune Suppression via Glucocorticoid-Stimulated Monocytes: A Novel Mechanism To Cope with Inflammation

Varga

Ehrchen

Brockhausen

et al. 2014

The Journal of Immunology

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“…[5][6][7] The current model stipulates that agonistic antibodies targeting GITR, OX40 and other costimulatory receptors on T cells directly enhance the cytotoxic effector function of T cells, while counteracting the immunosuppressive effects of immune-regulatory populations, such as regulatory T cells (Tregs). [8][9][10][11] We recently reported that an agonistic antibody targeting GITR (DTA-1) requires the engagement of activating FcgRs but not the inhibitory FcgR (FcgRIIB) to mediate antitumor activity in mice. 12 This finding challenges the notion that FcgRIIB-mediated crosslinking is generally required for the in vivo activities of agonistic antibodies targeting TNFRs.…”

mentioning

confidence: 99%

OX40 engagement depletes intratumoral Tregs via activating FcγRs, leading to antitumor efficacy

et al. 2014

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Antibodies targeting checkpoint inhibitors or co-stimulatory receptors on T cells have shown significant antitumor efficacy in preclinical and clinical studies. In mouse tumor models, engagement of activating Fcc receptor (FccR)-expressing immune cells was recently shown to be required for the tumoricidal activity of antibodies recognizing the tumor necrosis factor superfamily receptor (TNFR) GITR (CD357) and CTLA-4 (CD152). In particular, activating FccRs facilitated the selective elimination of intratumoral T-cell populations. However, it remains unclear whether FccRs contribute to the antitumor efficacy of other immunomodulatory antibodies. Here, we explored the mechanism of antitumor activity mediated by an agonistic antibody (clone OX86) to the co-stimulatory TNFR OX40 (CD134). OX40 was highly expressed by intratumoral T cells, particularly those of the FoxP3 þ regulatory T-cell (Treg) lineage. OX86 administration resulted in the depletion of intratumoral regulatory T cells in an activating FccR-dependent manner, which correlated with tumor regression. Together with previous data from our group and others, these findings support a mechanism whereby antibodies targeting antigens highly expressed by intratumoral T cells can mediate their elimination by FccR-expressing immune cells, and facilitate subsequent antitumor immunity. Agonistic antibodies targeting co-stimulatory tumor necrosis factor superfamily receptors (TNFRs) expressed by T cells, such as GITR (CD357) or OX40 (CD134), have been shown to enhance the proliferation and activation of isolated T cells. [1][2][3][4] Moreover, in preclinical tumor efficacy studies, these agonistic antibodies have shown potent tumoricidal activity. [5][6][7] The current model stipulates that agonistic antibodies targeting GITR, OX40 and other costimulatory receptors on T cells directly enhance the cytotoxic effector function of T cells, while counteracting the immunosuppressive effects of immune-regulatory populations, such as regulatory T cells (Tregs). [8][9][10][11] We recently reported that an agonistic antibody targeting GITR (DTA-1) requires the engagement of activating FcgRs but not the inhibitory FcgR (FcgRIIB) to mediate antitumor activity in mice. 12 This finding challenges the notion that FcgRIIB-mediated crosslinking is generally required for the in vivo activities of agonistic antibodies targeting TNFRs. [13][14][15] Importantly, DTA-1 administration triggered the rapid and selective elimination of intratumoral T cells, particularly those of the Treg lineage, as defined by FoxP3 expression. The extent of Treg depletion in the tumor microenvironment directly correlated with the antitumor efficacy. A similar mechanism was observed for antibodies targeting the non-TNFR immunoregulatory molecule CTLA-4. 12,16 A common feature of GITR and CTLA-4 is their high expression by intratumoral populations of T cells, with Tregs expressing the highest levels of each receptor. 12,17,18 Here, we investigated whether antibody-mediated intratumoral T-cell depletion might con...

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“…It has been originally discovered as up regulated in dexamethasone treated murine T-cell hybridomas [108]. It has very low expression in human T cells but constitutively expressed in human Treg [109]. Upon stimulation, naïve T cells and Treg upregulate GITR in a similar fashion to 4-1BB and OX40 suggesting their role in latter time points rather than early priming [110].…”

Section: Gitrmentioning

confidence: 99%

Emerging Targets in Cancer Immunotherapy: Beyond CTLA-4 and PD-1

et al. 2015

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Manipulation of co-stimulatory or co-inhibitory checkpoint proteins allows for the reversal of tumor-induced T-cell anergy observed in cancer. The field has gained credence given success with CTLA-4 and PD-1 inhibitors. These molecules include immunoglobulin family members and the B7 subfamily as well as the TNF receptor family members. PD-L1 inhibitors and LAG-3 inhibitors have progressed through clinical trials. Other B7 family members have shown promise in preclinical models. TNFR superfamily members have shown variable success in preclinical and clinical studies. As clinical investigation in tumor immunology gains momentum, the next stage becomes learning how to combine checkpoint inhibitors and agonists with each other as well as with traditional chemotherapeutic agents.

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Modulation of GITR for cancer immunotherapy

Cited by 129 publications

References 68 publications

Immune Suppression via Glucocorticoid-Stimulated Monocytes: A Novel Mechanism To Cope with Inflammation

Immune Suppression via Glucocorticoid-Stimulated Monocytes: A Novel Mechanism To Cope with Inflammation

OX40 engagement depletes intratumoral Tregs via activating FcγRs, leading to antitumor efficacy

Emerging Targets in Cancer Immunotherapy: Beyond CTLA-4 and PD-1

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