Myeloid cell–derived PROS1 inhibits tumor metastasis by regulating inflammatory and immune responses via IL-10

Maimon, Avi; Levi-Yahid, Victor; Ben‐Meir, Kerem; Halpern, Amit; Talmi, Ziv; Priya, Shivam; Mizraji, Gabriel; Mistriel-Zerbib, Shani; Berger, Michael; Baniyash, Michal; Loges, Sonja; Burstyn‐Cohen, Tal

doi:10.1172/jci126089

Cited by 52 publications

(41 citation statements)

References 89 publications

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“…Many mechanisms of immune regulation are shared between autoimmune and tumor settings, which led us to ask if regulation by MERTK signaling was altering the tumor-specific T cell response. TAM receptor family member–mediated regulation of the T cell response within the tumor is an active area of clinical and preclinical research ( Myers et al, 2019 ; Wu et al, 2018a ; Zhou et al, 2020 ; Maimon et al, 2021 ). MERTK-specific inhibition has been shown to suppress tumor growth in murine solid tumor models ( Sinik et al, 2019 ; Wu et al, 2018b ; Cook et al, 2013 ; Zhou et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites

Lindsay

Whitesell

Dew

et al. 2021

Journal of Experimental Medicine

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Understanding mechanisms of immune regulation is key to developing immunotherapies for autoimmunity and cancer. We examined the role of mononuclear phagocytes during peripheral T cell regulation in type 1 diabetes and melanoma. MERTK expression and activity in mononuclear phagocytes in the pancreatic islets promoted islet T cell regulation, resulting in reduced sensitivity of T cell scanning for cognate antigen in prediabetic islets. MERTK-dependent regulation led to reduced T cell activation and effector function at the disease site in islets and prevented rapid progression of type 1 diabetes. In human islets, MERTK-expressing cells were increased in remaining insulin-containing islets of type 1 diabetic patients, suggesting that MERTK protects islets from autoimmune destruction. MERTK also regulated T cell arrest in melanoma tumors. These data indicate that MERTK signaling in mononuclear phagocytes drives T cell regulation at inflammatory disease sites in peripheral tissues through a mechanism that reduces the sensitivity of scanning for antigen leading to reduced responsiveness to antigen.

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Section: Resultsmentioning

confidence: 99%

MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites

Lindsay

Whitesell

Dew

et al. 2021

Journal of Experimental Medicine

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“…FN1 (fibronectin 1) is involved in the process of cell adhesion and migration (Cai et al, 2018) and could rely on the TGF-β/PI3K/Akt pathway to promote chondrocyte differentiation and collagen production in fractured bones (Zhang et al, 2021). As for PROS1 (protein s), one of its roles is to inhibit tumor metastasis by mediating inflammation and immunization (Maimon et al, 2021). Downregulated SERPINE1 (serpin family E member 1) could accelerate the progression of inflammation (Yang et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Drug Discovery in Spinal Cord Injury With Ankylosing Spondylitis Identified by Text Mining and Biomedical Databases

Wang

et al. 2022

Front. Genet.

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Spinal cord injury (SCI) and ankylosing spondylitis (AS) are common inflammatory diseases in spine surgery. However, it is a project where the relationship between the two diseases is ambiguous and the efficiency of drug discovery is limited. Therefore, the study aimed to investigate new drug therapies for SCI and AS. First, text mining was used to obtain the interacting genes related to SCI and AS, and then, the functional analysis was conducted. Protein–protein interaction (PPI) networks were constructed by STRING online and Cytoscape software to identify hub genes. Last, hub genes and potential drugs were performed after undergoing drug–gene interaction analysis, and MicroRNA and transcription factors regulatory networks were also analyzed. Two hundred five genes common to “SCI” and “AS” identified by text mining were enriched in inflammatory responses. PPI network analysis showed that 30 genes constructed two significant modules. Ultimately, nine (SST, VWF, IL1B, IL6, CXCR4, VEGFA, SERPINE1, FN1, and PROS1) out of 30 genes could be targetable by a total of 13 drugs. In conclusion, the novel core genes contribute to a novel insight for latent functional mechanisms and present potential prognostic indicators and therapeutic targets in SCI and AS.

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“…MERTK signaling suppresses the NFkB pathway (Sen et al, 2007;Zhang et al, 2017;Camenisch et al, 1999).NFkB target genes include the pro-inflammatory cytokines TNF-, IL-1, IL-6, and IL-12p40 (Liu et al, 2017),which can all be expressed by mononuclear phagocytes and can be suppressed by the MERTK signaling axis (Zhang et al, 2017;Wallet et al, 2008;Camenisch et al, 1999;Maimon et al, 2021).Given the role of the islet milieu in controlling T cell responsiveness in the islets, (Friedman et al, 2014), this leads us to hypothesize that MERTK signaling creates a regulatory milieu by modulating soluble mediators such as cytokines that alter T cell scanning by tuning T cell adhesion and responsiveness to antigen.…”

Section: Discussionmentioning

confidence: 99%

“…Many mechanisms of immune regulation are shared between autoimmune and tumor settings, which led us to ask if regulation by MERTK signaling was altering the tumor-specific T cell response. TAM receptor family member mediated regulation of the T cell response within the tumor is an active area of clinical and pre-clinical research (Myers et al, 2019;Wu et al, 2018a;Zhou et al, 2020;Maimon et al, 2021). MERTK specific inhibition has been shown to suppress tumor growth in murine solid tumor models (Sinik et al, 2018;Wu et al, 2018b;Cook et al, 2013;Zhou et al, 2020).…”

Section: Mertk Regulates T Cell Arrest In a Solid Tumormentioning

confidence: 99%

MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites

Lindsay

Dew²,

Rodrı́guez³

et al. 2019

Preprint

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Understanding mechanisms of immune regulation is key to developing effective immunotherapies for autoimmunity and cancer; however, many regulatory mechanisms have not been elucidated. By analyzing T cell motility and activation at the disease site as well as disease progression, we examined the role of mononuclear phagocytes in driving regulation of effector T cells in type 1 diabetes and melanoma. We report that mononuclear phagocytes in the islets impair T cell responsiveness to antigen by preventing antigen-mediated T cell arrest.Mononuclear phagocytes in the autoimmune lesion express the TAM family receptor tyrosine kinase Mertk which functions in efferocytosis. Inhibition or deficiency of Mertk led to a release from T cell regulation characterized by enhanced T cell arrest in pre-diabetic islets and at the tumor site. This T cell arrest was accompanied by increased T cell-antigen presenting cell interactions as well as increased antigen experience and effector function by T cells in the islets.Notably, the effect of Mertk inhibition on T cell regulation was only seen at the disease site in the islets, not in draining lymph nodes. Inhibition of Mertk-dependent T cell regulation culminated in the rapid acceleration of autoimmune pathology and disease. In human islets, the number of Mertk-expressing cells were increased in remaining insulin-containing islets from type 1 diabetic patients, suggesting that they might have a protective role in human disease. These data indicate that Mertk signaling in mononuclear phagocytes drives T cell regulation that functions specifically at the disease site in peripheral tissues through a mechanism that prevents T cell arrest and response to antigen.

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Myeloid cell–derived PROS1 inhibits tumor metastasis by regulating inflammatory and immune responses via IL-10

Cited by 52 publications

References 89 publications

MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites

MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites

Drug Discovery in Spinal Cord Injury With Ankylosing Spondylitis Identified by Text Mining and Biomedical Databases

MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites

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