Plasmacytoid Dendritic Cells Promote Immunosuppression in Ovarian Cancer via ICOS Costimulation of Foxp3+ T-Regulatory Cells

Abstract Epithelial ovarian cancer (EOC) is the fifth most common cause of cancer death among women. Despite itsimmunogenicity, effective antitumor responsesare limited, due,inpart,to thepresence offorkheadbox protein3–positive (Foxp3 þ ) T regulatory (Treg) cells in the tumor microenvironment. However, the mechanisms thatregulate the accumulation andthe suppressive function oftheseFoxp3 þ Tregcells are poorlyunderstood. Here,wefoundthatthemajorityofFoxp3 þ TregcellsaccumulatinginthetumormicroenvironmentofEOCsbelongtothe subset of Foxp3 þ Treg cells expressing inducible costimulator (ICOS). The expansion and the suppressivefunction of these cells were strictly dependent on ICOS-L costimulation provided by tumor plasmacytoiddendriticcells(pDC).Accordingly,ICOS þ Foxp3 TregcellswerefoundtolocalizeinclosevicinityoftumorpDCs,and their number directly correlated with the numbers of pDCs in the tumors. Furthermore, pDCs and ICOS þ Foxp3 þ Tregcellswerefoundtobestrongpredictorsfordiseaseprogressioninpatientswithovariancancer,withICOS