Immunoregulatory functions and the therapeutic implications of GARP-TGF-β in inflammation and cancer

Metelli, Alessandra; Salem, Mohammad; Wallace, Caroline; Wu, Bill X.; Li, Anqi; Li, Xue; Li, Zihai

doi:10.1186/s13045-018-0570-z

Cited by 82 publications

(67 citation statements)

References 101 publications

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“…The function of GARP is to activate latent TGF-β in the close proximity of platelets. The GARP-TGFβ complex together with platelet-secreted lactate inhibited T cell immunity against both melanoma and colon cancer [ 42 , 43 ]. These data substantiate the notion that platelets interfere with the innate as well as with the adaptive immune system to tackle cancer cells.…”

Section: Role Of Platelets In Cancer Metastasismentioning

confidence: 99%

Role of platelets and platelet receptors in cancer metastasis

2018

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The interaction of tumor cells with platelets is a prerequisite for successful hematogenous metastatic dissemination. Upon tumor cell arrival in the blood, tumor cells immediately activate platelets to form a permissive microenvironment. Platelets protect tumor cells from shear forces and assault of NK cells, recruit myeloid cells by secretion of chemokines, and mediate an arrest of the tumor cell platelet embolus at the vascular wall. Subsequently, platelet-derived growth factors confer a mesenchymal-like phenotype to tumor cells and open the capillary endothelium to expedite extravasation in distant organs. Finally, platelet-secreted growth factors stimulate tumor cell proliferation to micrometastatic foci. This review provides a synopsis on the current literature on platelet-mediated effects in cancer metastasis and particularly focuses on platelet adhesion receptors and their role in metastasis. Immunoreceptor tyrosine-based activation motif (ITAM) and hemi ITAM (hemITAM) comprising receptors, especially, glycoprotein VI (GPVI), FcγRIIa, and C-type lectin-like-2 receptor (CLEC-2) are turned in the spotlight since several new mechanisms and contributions to metastasis have been attributed to this family of platelet receptors in the last years.

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Section: Role Of Platelets In Cancer Metastasismentioning

confidence: 99%

Role of platelets and platelet receptors in cancer metastasis

2018

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“…13). The release of the biologically active mature TGFb from this complex can occur by several factors including heat, acidic conditions, and integrins (14). Earlier reports have shown that GARP-deficient CD4 þ T cells mice did not impair the suppressive function of Treg cells in vitro (15) and that silencing of its expression by RNA interference does not significantly affect Foxp3 expression in expanded Tregs (16).…”

Section: Introductionmentioning

confidence: 99%

GARP Dampens Cancer Immunity by Sustaining Function and Accumulation of Regulatory T Cells in the Colon

et al. 2019

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Activated regulatory T (Treg) cells express the surface receptor glycoprotein-A repetitions predominant (GARP), which binds and activates latent TGFb. How GARP modulates Treg function in inflammation and cancer remains unclear. Here we demonstrate that loss of GARP in Treg cells leads to spontaneous inflammation with highly activated CD4 þ and CD8 þ T cells and development of enteritis. Treg cells lacking GARP were unable to suppress pathogenic T-cell responses in multiple models of inflammation, including T-cell transfer colitis. GARP À/À Treg cells were significantly reduced in the gut and exhibited a reduction in CD103 expression, a colon-specific migratory marker. In the coli-tis-associated colon cancer model, GARP on Treg cells dampened immune surveillance, and mice with GARP À/À Treg cells exhibited improved antitumor immunity. Thus, GARP empowers the functionality of Treg cells and their tissuespecific accumulation, highlighting the importance of cell surface TGFb in Treg function and GARP as a potential therapeutic target for colorectal cancer therapy. Significance: These findings uncover functions of membrane-bound TGFb and GARP that tune the activity of Treg cells, highlighting a potential treatment strategy in autoimmune diseases and cancer.

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“…Robust anti-cancer immune response consists of a series of stepwise immune events including the release of cancer-associated antigens, the processing and presentation of antigen presentation cells (APCs), the priming and activation of naïve T cells, the trafficking and migration of activated T cells, and the tumor-killing activity of effector cells [1,2]. Actually, the anti-cancer immune response is a highly complex process which could be strengthened or weakened by multiple factors such as immune editing, transforming growth factor-β (TGF-β) signaling, and immune checkpoints [3][4][5]. The balance between immunostimulatory and -inhibitory factors is crucial to maintain the immune homeostasis of host and clear the cancerderived materials [6].…”

Section: Introductionmentioning

confidence: 99%

The role of cancer-derived microRNAs in cancer immune escape

et al. 2020

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During malignant transformation, accumulated somatic mutations endow cancer cells with increased invasiveness and immunogenicity. Under selective pressure, these highly immunogenic cancer cells develop multiple strategies to evade immune attack. It has been well established that cancer cells could downregulate the expression of major histocompatibility complex, acquire alterations in interferon pathway, and upregulate the activities of immune checkpoint pathways. Besides, cancer cells secret numerous cytokines, exosomes, and microvesicles to regulate the functions and abundances of components in the tumor microenvironment including immune effector cells and professional antigen presentation cells. As the vital determinant of post-transcriptional regulation, microRNAs (miRNAs) not only participate in cancer initiation and progression but also regulate anti-cancer immune response. For instance, some miRNAs affect cancer immune surveillance and immune escape by interfering the expression of immune attack-associated molecules. A growing body of evidence indicated that cancer-derived immune modulatory miRNAs might be promising targets to counteract cancer immune escape. In this review, we summarized the role of some miRNAs in cancer immune escape and discussed their potential clinical application as treatment targets.

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Immunoregulatory functions and the therapeutic implications of GARP-TGF-β in inflammation and cancer

Cited by 82 publications

References 101 publications

Role of platelets and platelet receptors in cancer metastasis

Role of platelets and platelet receptors in cancer metastasis

GARP Dampens Cancer Immunity by Sustaining Function and Accumulation of Regulatory T Cells in the Colon

The role of cancer-derived microRNAs in cancer immune escape

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