Deletion of GARP on mouse regulatory T cells is not sufficient to inhibit the growth of transplanted tumors

Vermeersch, Elien; Liénart, Stéphanie; Collignon, A; Lucas, Sophie; Gallimore, Awen; Gysemans, Conny; Unutmaz, Derya; Vanhoorelbeke, Karen; Meyer, Simon F. De; Maes, Wim; Deckmyn, Hans

doi:10.1016/j.cellimm.2018.07.011

Cited by 10 publications

(12 citation statements)

References 31 publications

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“…In mice bearing CT26 or MC38 tumors, blocking anti-GARP:TGF-β1 mAbs did not induce tumor regression when administered alone, in line with observations in mice carrying a Treg-specific deletion of the Garp gene, which did not show reduced growth of MC38 or GL261 tumors by comparison to WT (Fig. 7 and Vermeersch et al 34 ). But when combined with anti-PD-1 mAbs, anti-GARP:TGF-β1 mAbs significantly increased the frequency of tumor rejection relative to anti-PD-1 alone.…”

Section: Discussionsupporting

confidence: 82%

Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer

et al. 2020

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TGF-β1, β2 and β3 bind a common receptor to exert vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Global TGF-β inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-β1 production by Tregs with antibodies against GARP:TGF-β1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARP:TGF-β1/PD-1 blockade are immune-mediated, do not require FcγR-dependent functions and increase effector functions of anti-tumor CD8+ T cells without augmenting immune cell infiltration or depleting Tregs within tumors. We find GARP-expressing Tregs and evidence that they produce TGF-β1 in one third of human melanoma metastases. Our results suggest that anti-GARP:TGF-β1 mAbs, by selectively blocking a single TGF-β isoform emanating from a restricted cellular source exerting tumor-promoting activity, may overcome resistance to PD-1/PD-L1 blockade in patients with cancer.

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Section: Discussionsupporting

confidence: 82%

Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer

et al. 2020

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“…Deletion of GARP on mouse Tregs is not sufficient to inhibit the growth of transplanted tumors. They found the suppressive function of Tregs was not affected by knockout of garp in Tregs [32]. Further studies are needed to reveal the mechanisms responsible for suppressive function of LAP + Tregs.…”

Section: Discussionmentioning

confidence: 99%

Human LAP⁺GARP⁺FOXP3⁺ regulatory T cells attenuate xenogeneic graft versus host disease

Song¹,

Pham²,

Cooper³

et al. 2019

Theranostics

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Adoptive transfer of regulatory T cells (FOXP3 + Tregs) has been developed as a potential curative immune therapy to prevent and treat autoimmune and graft-versus-host diseases (GVHD). A major limitation that has hindered the use of Treg immunotherapy in humans is the difficulty of consistently isolating and obtaining highly purified Tregs after ex vivo expansion. Methods : We isolated bona fide Tregs from expansion cultures based on their selective surface expression of latency-associated peptide (LAP). The TCR Vβ diversity and intracellular cytokine production of Tregs were determined by flow cytometer. The TSDR methylation was determined by epigenetic human FOXP3 qPCR Assay. Their in vitro and in vivo potency was confirmed with suppression assay and humanized xenogeneic GVHD (xGVHD) murine model, respectively. Results : LAP + repurification results in >90% LAP + FOXP3 + Tregs, leaving behind FOXP3 - and FOXP3 + nonTregs within the LAP - population. After 4-week expansion, the LAP + Tregs were >1 billion cells, highly suppressive and anergic in vitro , >90% demethylated in the TSDR and able to maintain TCR Vβ diversity. In the xGVHD model, exogenous CD25 - PBMC administered alone results in a median survival of 32 days. The co-transfer of LAP + Tregs increased median survival to 47 days, while the LAP parent (CD25 + ) and LAP - nonTregs had median survival of 39 and 31 days, respectively. Conclusions : These preclinical data together provide evidence that LAP + Tregs are highly purified with fully suppressive function for cell therapy. This population results in a more effective and safer product for immunotherapy to treat GVHD and provides the necessary preclinical data for transition into a clinical trial with LAP + Tregs to prevent or treat GVHD and other autoimmune diseases.

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“…Indeed, one of the features of Tregs is to express at their surface high amounts of the protein GARP, which can bind latent complex, then present it to αvβ8 integrin and thus contribute to the activation of secreted latent TGF-β 26 , 32 . However, in contrast to the absence of Itgb8, the deletion in Tregs of lrrc32, which encodes for GARP, is not su cient to affect tumor growth 33 . While GARP expression on Tregs contributes to the activation of secreted latent complexes, that of Itgβ8 contributes to the activation of latent complexes stored in the TME.…”

Section: Discussionmentioning

confidence: 93%

Cooperation between Cancer Cells and Regulatory T Cells to Promote Immune-escape through Integrin αvβ8-Mediated TGF-β Activation

Laine

Labiad

Hernandez-Vargas³

et al. 2021

Preprint

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Among the strategies allowing cancer cells to escape the immune system, the presence of TGF-b in the tumor micro-environment is one of the most potent. However, TGF-b is secreted in an inactive form and mechanisms responsible for its activation within the tumor remain unknown. Here, we demonstrate that regulatory T cells (Tregs) compose the main cells expressing the b8 chain of avb8 integrin (Itgb8) in the tumors and that the Itgb8pos Treg population activates TGF-b produced by the cancer cells and stored in the tumor micro-environment. Itgb8 ablation in Tregs impaired TGF-b signaling in T lymphocytes present in the tumor but not in the tumor draining lymph nodes. The cytotoxic function of CD8pos T lymphocytes infiltrating the tumors was subsequently exacerbated leading to an efficient control of the tumor growth. Similar observations were made in patient tumors after anti-Itgb8 antibody treatment. Thus, this study reveals that Tregs work in concert with cancer cells to produce bioactive-TGF-b and create a powerful-immunosuppressive micro-environment.

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Deletion of GARP on mouse regulatory T cells is not sufficient to inhibit the growth of transplanted tumors

Cited by 10 publications

References 31 publications

Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer

Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer

Human LAP⁺GARP⁺FOXP3⁺ regulatory T cells attenuate xenogeneic graft versus host disease

Cooperation between Cancer Cells and Regulatory T Cells to Promote Immune-escape through Integrin αvβ8-Mediated TGF-β Activation

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Deletion of GARP on mouse regulatory T cells is not sufficient to inhibit the growth of transplanted tumors

Cited by 10 publications

References 31 publications

Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer

Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer

Human LAP+GARP+FOXP3+ regulatory T cells attenuate xenogeneic graft versus host disease

Cooperation between Cancer Cells and Regulatory T Cells to Promote Immune-escape through Integrin αvβ8-Mediated TGF-β Activation

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Human LAP⁺GARP⁺FOXP3⁺ regulatory T cells attenuate xenogeneic graft versus host disease