Monocyte Stabilin-1 Suppresses the Activation of Th1 Lymphocytes

Palani, Senthil; Elima, Kati; Ekholm, Eeva; Jalkanen, Sirpa; Salmi, Marko

doi:10.4049/jimmunol.1500257

Cited by 41 publications

(59 citation statements)

References 34 publications

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“…In fact, blocking Clever-1 skewed TAMs toward an immunostimulatory phenotype with increased MHC II expression and IL12p40 secretion, thus enabling efficient antigen presentation and improving tumor control by boosting infiltration of CD8 þ T cells, respectively (47). Similarly, Clever-1 knockdown in human monocytes increases their ability to reactivate T cells in antigen recall assays (11). Intriguingly, the aforementioned changes were accompanied by increased CD206 expression by MHC II high TAMs.…”

Section: Discussionmentioning

confidence: 99%

“…Recent reports by us and others indicate that Clever-1 also advantages tumor progression (8)(9)(10)17). However, the proposed tumorigenic mechanisms center on the paradigm of Clever-1 as an adhesion and scavenger receptor and do not explain the direct immunosuppressive functions of Clever-1 þ monocytes and macrophages we have recently described (11,18,19). Mechanistic details explaining how macrophage Clever-1 regulates innate-adaptive immune crosstalk and cancer-related inflammation are not fully understood.…”

Section: Introductionmentioning

confidence: 89%

“…Common lymphatic endothelial and vascular endothelial receptor-1 (Clever-1)-encoded by the Stab1 gene and also called Stabilin-1 or Feel-1-is a conserved, multifunctional adhesion and scavenger receptor expressed by subsets of endothelial cells, immunosuppressive macrophages, and TAMs (7)(8)(9)(10)(11). Clever-1 mediates cell adhesion and the scavenging and intracellular trafficking of its ligands (7,(12)(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

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Immunotherapeutic Blockade of Macrophage Clever-1 Reactivates the CD8+ T-cell Response against Immunosuppressive Tumors

Viitala

Virtakoivu

Tadayon

et al. 2019

Clinical Cancer Research

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Purpose: As foremost regulators of cancer-related inflammation and immunotherapeutic resistance, tumor-associated macrophages have garnered major interest as immunotherapeutic drug targets. However, depletory strategies have yielded little benefit in clinical studies to date. An alternative approach is to exploit macrophage plasticity and "reeducate" tumorigenic macrophages toward an immunostimulatory phenotype to activate the host's antitumor immunity.Experimental Design: We investigated the role of the macrophage scavenger receptor common lymphatic endothelial and vascular endothelial receptor-1 (Clever-1) on tumor growth in multiple mouse cancer models with inflammatory and noninflammatory characteristics by using conditional knockouts, bone marrow chimeras, and cell depletion experiments. In addition, the efficacy of immunotherapeutic Clever-1 blockade as monotherapy or in combination with anti-PD-1 was tested.Results: Genetic deficiency of macrophage Clever-1 markedly impaired solid tumor growth. This effect was mediated by macrophages that became immunostimulatory in the absence of Clever-1, skewing the suppressive tumor microenvironment toward inflammation and activating endogenous antitumor CD8 þ T cells. Comparable effects were achieved with immunotherapeutic blockade of Clever-1. Notably, these effects were similar to those achieved by PD-1 checkpoint inhibition. Moreover, combining anti-Clever-1 with anti-PD-1 provided synergistic benefit in aggressive, nonresponsive tumors.Conclusions: These findings demonstrate the importance of macrophages in mediating antitumor immune responses and support the clinical evaluation of immunotherapeutic Clever-1 blockade as a novel cancer treatment strategy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Immunotherapeutic Blockade of Macrophage Clever-1 Reactivates the CD8+ T-cell Response against Immunosuppressive Tumors

Viitala

Virtakoivu

Tadayon

et al. 2019

Clinical Cancer Research

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“…Скавенджер-рецептор stabilin-1 представляет собой трансмембранный белок с небольшим цитоплазматическим доменом на С-конце, единым трансмембранным доменом и большой внеклеточной частью. Stabilin-1 рецептор участвует в захвате цитокинов, ростовых факторов, модифицированных липопротеидов, фагоцитозе апоптозных телец, компонентов экстрацеллюлярного матрикса без индуцирования провоспалительных реакций [28,29]. В ряде работ было показано, что stabilin-1 обладает противовоспалительной активностью и препятствует развитию фиброза при хроническом воспалении [29,30].…”

Section: оригинальные статьи § введениеunclassified

Dynamics of brain CD68+ and stabilin-1+ macrophage infiltration in patients with myocardial infarction

et al. 2019

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Te aim of the study was to evaluate the temporal dynamics of brain CD68+ and stabilin-1+ macrophage infltration in patients with fatal myocardial infarction (MI) type 1.Materials and Methods. Te study included 31 patients with fatal MI type I. Te control group comprised 10 patients of 18–40 age group who died from injuries incompatible with life. Patients with MI were divided into two groups. Group 1 comprised patients who died during the frst 72 hours of MI, group 2 comprised patients who died on days 4‒28. Macrophage infltration in the brain was assessed by immunohistochemical analysis. We used CD68 as a marker for the cells of the macrophage lineage and stabilin-1 as an M2-like macrophage biomarker.Results. In group 1 the number of brain CD68+ macrophages was signifcantly higher than in the control group. In group 2 the intensity of brain CD68+ cells infltration was lower than in group 1 and higher than in the control group. Tere was a small amount of stabilin-1+ macrophages in the brain of healthy people, as well as of patients who died from MI. Tere were no signifcant diﬀerences in the number of stabilin-1+ cells between group 1 and group 2. Correlation analysis revealed the presence of positive correlation between the number of CD68 + macrophages in the infarct, peri-infarct, and non-infarct areas of the myocardium and the number of CD68+ macrophages in the brain in patients with MI. Tere were not correlations between the number of CD68 + and stabilin-1+ cells and the presence of diabetes mellitus, history of stroke, history of MI, and pre-infarction angina.Conclusion. Te number of brain CD68+ macrophages signifcantly increased during the frst three days of MI. Te number of brain stabilin-1+ macrophages did not increase and did not diﬀer from the control values. We observed a positive correlation between the number of CD68+ macrophages in the brain and myocardium.

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“…Tim-3 was required for the upregulation of these chemokines in tumoral Tregs (Figure 5C). The analysis indicated that Tim-3 was critical for the expression of an array of immune suppressive effector genes such as Calca, Fcrl6, Stab1, F2rl2, Il10, Ramp1, Cd200, Lag3, Lgals4, Fasl, Entpd1(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). Interestingly, αvβ8 integrin mRNAs were also expressed at a higher level in Tim-3 sufficient Tregs, suggesting Tim-3 expression confers Treg cells the ability to activate TGF-β(39)(40)(41).…”

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confidence: 99%

Tim-3 drives tissue Treg effector function to promote neonatal immune tolerance and tumor-induced immune suppression

Yang¹,

Wu²,

W³

et al. 2020

Preprint

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Tissue regulatory T cells (Treg) are a key player in preventing immune pathology and shaping the immune suppressive tumor microenvironment (TME). The signaling molecules that uniquely regulate tissue Treg are not well understood. Here, we show that Tim-3 was predominantly expressed in Treg cells in both normal and tumor tissues. Notably, Tim-3 deficiency in Tregs led to the development of severe signs of autoimmune diseases in neonatal mice, indicating a crucial role of Tim-3 in establishing immune tolerance in early life. In addition, deletion of Tim-3 on Tregs resulted in reduced numbers and suppressor activities of tumoral Tregs and an increase in antitumor immune responses. A gene profiling study revealed the requirement of Tim-3 in upregulation of effector Treg genes encoding immune inhibitory molecules, chemokine receptors for tissue residency, chemokines, and cytokines. Moreover, Tim-3 deficiency in Tregs and treatment with PD-1 mAbs synergistically inhibited tumor growth. Our study demonstrates the essential role of Tim-3 in driving tissue effector Treg-mediated immune suppression.

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Monocyte Stabilin-1 Suppresses the Activation of Th1 Lymphocytes

Cited by 41 publications

References 34 publications

Immunotherapeutic Blockade of Macrophage Clever-1 Reactivates the CD8+ T-cell Response against Immunosuppressive Tumors

Immunotherapeutic Blockade of Macrophage Clever-1 Reactivates the CD8+ T-cell Response against Immunosuppressive Tumors

Dynamics of brain CD68+ and stabilin-1+ macrophage infiltration in patients with myocardial infarction

Tim-3 drives tissue Treg effector function to promote neonatal immune tolerance and tumor-induced immune suppression

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