title: 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(+) T cells along with increased numbers of regulatory T cells (Treg) and plasmacytoid dendritic cells (pDC) that facilitate immune escape and correlate with poor prognosis. Here, we report that inducible costimulatory molecule (ICOS), a T cell costimulatory molecule of the CTLA4/PD1/CD28 family, is expressed mostly by tumor-associated Treg in primary breast tumors. A large proportion of these ICOS(+) Treg were Ki67(+) and this evident proliferative expansion was found to rely on interactions with tumor-associated pDC. Indeed, tumor-associated Treg highly expanded in presence of pDC but failed to proliferate under CD3/CD28 signal. In vitro experiments revealed that the addition of a neutralizing anti-ICOS antibody blocked pDC-induced Treg expansion and interleukin-10 secretion by memory CD4(+) T cells, establishing a pivotal role for ICOS in this process. Supporting these findings, the presence of ICOS(+) cells in clinical specimens of breast cancer correlated with a poor prognosis. Together, our results highlight an important relationship between Treg and pDC in breast tumors, and show that ICOS/ICOS-L interaction is a central event in immunosuppression of tumor-associated memory CD4(+) T cells. These findings strongly rationalize antibody-mediated ICOS blockade as a powerful clinical strategy to correct immune escape and promote therapeutic responses in breast cancer.
authors.affiliation: Team 11, Cancer Research Center of Lyon, INSERM, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Faget
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bendriss-Vermare
authors.forename: Michael
authors.initials: M
authors.lastname: Gobert
authors.forename: Isabelle
authors.initials: I
authors.lastname: Durand
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
authors.forename: Cathy
authors.initials: C
authors.lastname: Biota
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.forename: Sophie
authors.initials: S
authors.lastname: Goddard-Leon
authors.forename: Emilie
authors.initials: E
authors.lastname: Lavergne
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chabaud
authors.forename: Jean Yves
authors.initials: JY
authors.lastname: Blay
authors.forename: Christophe
authors.initials: C
authors.lastname: Caux
authors.forename: Christine
authors.initials: C
authors.lastname: Ménétrier-Caux
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation; D012189:Retrospective Studies; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; C556692:ICOS protein, human; C498514:ICOSLG protein, human; C508609:IL10 protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10; D007371:Interferon-gamma