<i>In silico</i>
            identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination

Bayry, Jagadeesh; Tchilian, Elma; Davies, Matthew N.; Forbes, Emily K.; Draper, Simon J.; Kaveri, Srini V.; Hill, Adrian V. S.; Kazatchkine, Michel D.; Beverley, Peter C. L.; Flower, Darren R.; Tough, David F.

doi:10.1073/pnas.0803453105

Cited by 115 publications

(111 citation statements)

References 44 publications

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“…9 In our model, however, this mechanism appeared to have no effect on the Treg elevation, since the treatment failed to significantly decrease the proportion of tumor-infiltrating Treg. Together, these results suggest that the initial source of Treg in the tumor tissue could be either migrated Treg or induced Treg population.…”

Section: Discussioncontrasting

confidence: 51%

“…For instance, in many tumor entities, cancer cells and tumor-associated macrophages and dendritic cells produce the chemokines CCL22 and CCL17 that preferentially attract Treg through the CCR4 receptor. 8 , 9 However, several tumor models exhibit Treg expansion in both tumor and draining lymph nodes, which suggests that mechanisms other than migration, such as local proliferation and conversion, contribute to Treg accumulation. 10 , 11 There is a large body of evidence indicating that antigenic stimulation of naïve Tcon in the presence of TGF-b and interleukin-2 (IL-2) triggers their conversion into iTreg in the tumor and draining lymph nodes.…”

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confidence: 99%

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Low‐dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer

Shevchenko

Karakhanova

Soltek

et al. 2013

Intl Journal of Cancer

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms with extremely poor prognosis and a low survival rate. Immunosuppressive cell populations, e.g. regulatory T cells (Treg), appear to be important in PDAC, contributing to patient's poor prognosis. Therefore, we investigated the PDAC microenvironment with a focus on conventional and regulatory T cells in view of their potential therapeutic importance. We found that tumors from the murine Panc02 orthotopic model of PDAC were infiltrated with high numbers of Treg. Remarkably, these cells exhibited the effector/memory phenotype, suggesting their enhanced suppressive activity and higher proliferation capacity. Although we observed a steady increase in transforming growth factor-b (TGF-b) levels in the tumors, treatment with a specific inhibitor of TGF-b receptor I kinase failed to abrogate Treg accumulation. A CCR4 antagonist did not affect Treg percentage in the tumor either. However, intense Treg cell division in the tumor microenvironment was demonstrated, suggesting local proliferation as a major mechanism of Treg accumulation in PDAC. Notably, this accumulation was reduced by low-dose gemcitabine administration, resulting in a modestly increased survival of PDAC mice. Our results provide an insight into mechanisms of immunosuppression in PDAC, suggesting an important role for proliferative expansion of effector/memory Treg. Low-dose gemcitabine therapy selectively depletes Treg, providing a basis for new modalities of PDAC therapy.Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms having extremely poor prognosis with a 5-year survival rate of <1% and a median survival of 6 months. Even after surgical intervention, the 5-year survival rate is at best 15% without adjuvant therapy or 25% with adjuvant chemotherapy. 1 In contrast to other malignancies, pancreatic cancer is highly resistant to chemotherapy and targeted therapy. The molecular mechanisms that determine treatment resistance are poorly understood.

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Section: Discussioncontrasting

confidence: 51%

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confidence: 99%

Low‐dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer

Shevchenko

Karakhanova

Soltek

et al. 2013

Intl Journal of Cancer

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146

122

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“…Second, we tested the effect exerted by a CCR4 antagonist on Treg cell homing. DC-tg mice adoptively transferred with 2a T cells were systemically treated with the potent CCR4 antagonist, AF399/42018025, 37 to break down the possible CCL22-mediated mechanism of retention, and Treg cells enumerated 3 days later. As shown in Figure 3A,D, a strong reduction in Foxp3 ϩ CD25 ϩ 2a T-cell numbers was observed in CLNs.…”

Section: Ccl22 Contributes To the Retention Of Itreg Cells In Clnsmentioning

confidence: 99%

Migratory, and not lymphoid-resident, dendritic cells maintain peripheral self-tolerance and prevent autoimmunity via induction of iTreg cells

Vitali¹,

Mingozzi²,

Broggi³

et al. 2012

Blood

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IntroductionInduction and maintenance of T-cell tolerance toward self-antigens is vital to prevent autoimmunity. To this purpose, many different overlapping and nonoverlapping mechanisms of T-cell tolerization exist, both at central and peripheral levels. [1][2][3][4][5] A common vision of how dendritic cells (DCs) contribute to the induction and maintenance of peripheral CD4 ϩ T-cell tolerance is that, in resting conditions, immature DCs, expressing low levels of signal 1 (specificity) and low or no levels of signal 2 (costimulation), are able to induce T-cell unresponsiveness.However, the effective knowledge concerning the contribution of DCs in inducing and maintaining CD4 ϩ T-cell tolerance in peripheral lymphoid organs derives from the selective analysis of specific DC subpopulations. In particular, CD205 ϩ DCs are able to induce CD4 ϩ T-cell tolerance in conditions of suboptimal activation. [6][7][8][9] Moreover, steady-state migratory DC (ssmDC) subpopulations from the gut and the skin, phenotypically CD103 ϩ and CD103 Ϫ , respectively, mediate the conversion of naive T cells into Foxp3 ϩ regulatory T cells (iTreg) in a retinoic acid (RA)-dependent manner. [10][11][12][13] Because the lymph constantly carries peptides for loading on both migratory and lymphoid tissue resident immature DCs in a dose range suitable for tolerization, 14 it cannot be excluded that, in addition to the analyzed populations and in agreement with the common vision, all conventional immature DCs can induce autoantigen specific CD4 ϩ T-cell tolerance in the periphery. Therefore, it was relevant to know whether DCs in general are able to induce T-cell tolerance at the steady state or whether this is a prerogative of specialized subsets. We investigated this question using an experimental system where antigen presentation, in contrast to previous studies, is not a priori confined to a specific DC subpopulation but is extended to all conventional DC subtypes. Specifically, we adopted the 2a T transgenic animal model. 15 In this experimental system, T-cell receptor (TCR) transgenic T cells (2a T cells) recognize a portion of the CH3 region (435-451) of the IgG2a b , the Bpep, in association with the MHC molecule, I-A d . We also generated a mouse model in which the Bpep was presented by CD11c ϩ cells that include all conventional DC subtypes. By performing a systematic study of the behavior of naive autoantigen-specific T cells after interaction with all conventional CD11c ϩ DCs in homeostatic conditions, we found that DCs are able to induce CD4 ϩ T-cell tolerance by promoting the conversion of autoantigen-specific naive T cells into iTreg cells. Among the different DC subtypes, ssmDCs possess the unique ability to induce antigen-specific iTreg cells in an RA-dependent manner. Diversely, lymphoid tissue resident DCs do not show this capacity. Therefore, iTreg cells develop solely in lymph nodes and not in the spleen, which does not host the migratory DC subtype. We also show that iTreg cells that are newly generated in lymph nodes do n...

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“…Tregs migrate in response to several CC motif chemokines (16,17). In particular, CCL22 is a prominent chemotactic agent driving Treg accumulation in tumors, and antagonism of either CCL22 or its receptor (CCR4) has potent antitumor effects (18)(19)(20)(21). Similarly, CCL22 expression in allografts promotes Treg accumulation and prevents graft rejection (20,22,23), and induction of CCL22 in the pancreas of nonobese diabetic mice promoted Treg accumulation, protecting against tissue destruction and autoimmune diabetes (24).…”

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confidence: 99%

Marginal zone CD169⁺macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance

Ravishankar

Shinde

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

116

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Tolerance to apoptotic cells is essential to prevent inflammatory pathology. Though innate responses are critical for immune suppression, our understanding of early innate immunity driven by apoptosis is lacking. Herein we report apoptotic cells induce expression of the chemokine CCL22 in splenic metallophillic macrophages, which is critical for tolerance. Systemic challenge with apoptotic cells induced rapid production of CCL22 in CD169 + (metallophillic) macrophages, resulting in accumulation and activation of FoxP3 + Tregs and CD11c + dendritic cells, an effect that could be inhibited by antagonizing CCL22-driven chemotaxis. This mechanism was essential for suppression after apoptotic cell challenge, because neutralizing CCL22 or its receptor, reducing Treg numbers, or blocking effector mechanisms abrogated splenic TGF-β and IL-10 induction; this promoted a shift to proinflammatory cytokines associated with a failure to suppress T cells. Similarly, CCR4 inhibition blocked long-term, apoptotic cell-induced tolerance to allografts. Finally, CCR4 inhibition resulted in a systemic breakdown of tolerance to self after apoptotic cell injection with rapid increases in anti-dsDNA IgG and immune complex deposition. Thus, the data demonstrate CCL22-dependent chemotaxis is a key early innate response required for apoptotic cell-induced suppression, implicating a previously unknown mechanism of macrophage-dependent coordination of early events leading to stable tolerance.transplantation | autoimmunity | migration | spleen | regulation

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In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination

Cited by 115 publications

References 44 publications

Low‐dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer

Low‐dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer

Migratory, and not lymphoid-resident, dendritic cells maintain peripheral self-tolerance and prevent autoimmunity via induction of iTreg cells

Marginal zone CD169⁺macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance

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In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination

Cited by 115 publications

References 44 publications

Low‐dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer

Low‐dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer

Migratory, and not lymphoid-resident, dendritic cells maintain peripheral self-tolerance and prevent autoimmunity via induction of iTreg cells

Marginal zone CD169+macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance

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Marginal zone CD169⁺macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance