ICOS-Ligand Expression on Plasmacytoid Dendritic Cells Supports Breast Cancer Progression by Promoting the Accumulation of Immunosuppressive CD4+ T Cells

Faget, Julien; Bendriss‐Vermare, Nathalie; Gobert, Michael; Durand, Isabelle; Olive, Daniel; Biota, Catherine; Bachelot, Thomas; Treilleux, Isabelle; Goddard-Léon, Sophie; Lavergne, Emilie; Chabaud, Sylvie; Blay, Jean‐Yves; Caux, Christophe; Ménétrier‐Caux, Christine

doi:10.1158/0008-5472.can-12-2409

Cited by 181 publications

(162 citation statements)

References 50 publications

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“…Furthermore, several studies have shown that ICOSL-expressing plasmacytoid DCs in the tumor microenvironment can promote the immunosuppressive function and accumulation of Tregs via ICOS costimulation (59,60). Together with these findings, our data point to a plausible model in which Treg subsets in the tumor undergo activation and express ICOS, followed by ICOS costimulation via the interaction with ICOSL + plasmacytoid DCs (60,61) and/or melanoma cells in the tumor microenvironment that further drives ICOS + Treg activation (38). Upon HD IL-2 therapy, these activated ICOS + Tregs are then driven to divide rapidly.…”

Section: Methodssupporting

confidence: 76%

“…Alternatively, the ICOS/ ICOSL pathways driving gene expression in Tregs and their activation may be responsible for the differential ICOS + Treg expansion between IL-2 responders and nonresponders regulating the activity of antitumor effector cells (especially NK cells) that may counterbalance the "Treg surge" during the initial cycles of HD IL-2 therapy. About 50% of tumors from patients with metastatic melanoma expressed ICOSL (38), suggesting that differential expression of this and other costimulatory molecules by tumor cells or APC may drive ICOS + Treg expansion to different extents (60)(61)(62)(63)(64)(65). Tracking ICOSL and ICOS + Tregs in tumor biopsies in future studies should help shed light on this possibility.…”

Section: Methodsmentioning

confidence: 99%

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IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients

Sim¹,

Martín‐Orozco

Jin³

et al. 2013

J. Clin. Invest.

188

168

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Section: Methodssupporting

confidence: 76%

Section: Methodsmentioning

confidence: 99%

IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients

Sim¹,

Martín‐Orozco

Jin³

et al. 2013

J. Clin. Invest.

188

168

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“…In tumor microenvironment, pDCs exhibit a tolerogenic phenotype characterized by low costimulatory molecule expression and low IFNI production, and promote tumor growth possibly through Treg induction (10)(11)(12)(13). In contrast, specific Ag delivery to pDCs using BST2 in combination with TLR agonists induced protective immunity against tumor growth (4).…”

Section: Introductionmentioning

confidence: 99%

Ag-Presenting CpG-Activated pDCs Prime Th17 Cells That Induce Tumor Regression

et al. 2014

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Plasmacytoid dendritic cells (pDC) rapidly and massively produce type I IFN and other inflammatory cytokines in response to foreign nucleic acids, thereby indirectly influencing T-cell responses. Moreover, antigen (Ag)-presenting pDCs directly regulate T-cell differentiation. Depending on the immune environment, pDCs exhibit either tolerogenic or immunogenic properties. Here, we show that CpG-activated pDCs promote efficient Th17 differentiation. Indeed, Th17 responses are defective in mice selectively lacking MHCII on pDCs upon antigenic challenge. Importantly, in those mice, the frequency of Th17 cells infiltrating solid tumors is impaired. As a result, the recruitment of infiltrating leukocytes in tumors, including tumor-specific cytotoxic T lymphocytes (CTL), is altered and results in increased tumor growth. Importantly, following immunization with tumor Ag and CpG-B, MHCII-restricted Ag presentation by pDCs promotes the differentiation of antitumor Th17 cells that induce intratumor CTL recruitment and subsequent regression of established tumors. Our results highlight a new role for Ag presenting activated pDCs in promoting the development of Th17 cells and impacting on antitumor immunity. Cancer Res; 74(22); 6430-40. Ó2014 AACR.

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“…Since GITR-targeted immunotherapy has been shown to positively impact tumor immunity, this preliminary observation may deserve further attention [35,36]. The role of other Treg-associated molecules such as ICOS (inducible costimulatory molecules) in immune escape of glioma, remains to be elucidated [37].…”

Section: Discussionmentioning

confidence: 99%

Circulating T regulatory cells migration and phenotype in glioblastoma patients: an in vitro study

Vasco¹,

Canazza²,

Rizzo³

et al. 2013

J Neurooncol

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Glioblastoma multiforme (GBM) is the most aggressive primary human brain tumor. The relatively high amount of T regulatory lymphocytes present in the tumor, contributes to the establishment of an immunosuppressive microenvironment. Samples of peripheral blood were collected from GBM patients and healthy controls and a purified population of Treg (CD4 ? /CD25 bright ) was isolated using flow cytometric cell sorting. Treg migrating capacities toward human glioma cell line conditioned medium were evaluated through an in vitro migration test. Our data show that supernatants collected from GBM cell lines were more attractant to Treg when compared to complete standard medium. The addition of an anti-CCL2 antibody to conditioned medium decreased conditioned mediumdepending Treg migration, suggesting that CCL2 (also known as Monocyte Chemoattractant Protein, MCP-1) is implicated in the process. The number of circulating CD4? /lL or Treg/lL was similar in GBM patients and controls. Specific Treg markers (FOXP3; CD127; Helios; GITR; CTLA4; CD95; CCR2, CCR4; CCR7) were screened in peripheral blood and no differences could be detected between the two populations. These data confirm that the tumor microenvironment is attractive to Treg, which tend to migrate toward the tumor region changing the immunological response. Though we provide evidence that CCL2 is implicated in Treg migration, other factors are needed as well to provide such effect.

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ICOS-Ligand Expression on Plasmacytoid Dendritic Cells Supports Breast Cancer Progression by Promoting the Accumulation of Immunosuppressive CD4+ T Cells

Abstract: Human breast tumors are infiltrated by memory CD4 þ T cells along with increased numbers of regulatory T

Cited by 181 publications

References 50 publications

IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients

IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients

Ag-Presenting CpG-Activated pDCs Prime Th17 Cells That Induce Tumor Regression

Circulating T regulatory cells migration and phenotype in glioblastoma patients: an in vitro study

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