Objective Although tumor tissues can be infiltrated by T cells specific for tumor antigens, the effector functions of these lymphocytes are generally suppressed by CD4+ regulatory T cells (Tregs). Since tumor infiltrating Tregs can display function heterogeneity, depending on both the tumor type and the inflammatory milieu, only inhibition of the right Treg activity should result in the unleash of an effective anti-tumor T cell responses. Experimental plan: To identify the Tregs that truly inhibit anti-tumor T cells, we will profile by RNA-Seq the transcriptome of Tregs infiltrating both tumor and healthy tissues. In particular, we will focus on LncRNAs and the gene networks they modulate, since they have recently emerged as relevant epigenetic regulators of cell differentiation and identity. We will exploit this new knowledge to create a panel of regulatory transcripts, which will be assessed at single cell level on tumor infiltrating Tregs, so to determine the association of specific transcripts with different Treg populations. Since downregulation of specific lncRNAs might be an efficient way to inhibit the “unwanted” Tregs at tumor sites, we aim at targeting lncRNAs uniquely expressed in these Tregs and propose to develop AsiCs, chimeric molecules composed by an aptamer, single stranded oligonucleotides that bind to cell surface markers, and a siRNA, short RNAs downregulating specific lncRNAs. Deliverables and conclusions: this proposal will provide new knowledge on tumor infiltrating Tregs possibly allowing definition of molecular signatures of Tregs with either positive or negative effects on antitumor T cell responses. Moreover, we will develop new molecules that specifically target lncRNAs of interest and that will help identifying new antitumor therapeutic targets. In conclusion, the possibility to modulate Tregs effector functions may not only offer new anti-tumor therapy but more in general may be relevant to any immunomodulatory therapeutic strategies. Fields of science natural sciencesbiological sciencesgeneticsRNA Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-CG-2013-LS7 - ERC Consolidator Grant - Diagnostic Tools, Therapies and Public Health Call for proposal ERC-2013-CoG See other projects for this call Funding Scheme ERC-CG - ERC Consolidator Grants Host institution UNIVERSITA DEGLI STUDI DI MILANO EU contribution € 648 900,00 Address Via Festa Del Perdono 7 20122 Milano Italy See on map Region Nord-Ovest Lombardia Milano Activity type Higher or Secondary Education Establishments Principal investigator Massimiliano Pagani (Prof.) Administrative Contact Gerardo D'errico (Mr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (2) Sort alphabetically Sort by EU Contribution Expand all Collapse all UNIVERSITA DEGLI STUDI DI MILANO Italy EU contribution € 648 900,00 Address Via Festa Del Perdono 7 20122 Milano See on map Region Nord-Ovest Lombardia Milano Activity type Higher or Secondary Education Establishments Principal investigator Massimiliano Pagani (Prof.) Administrative Contact Gerardo D'errico (Mr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data FONDAZIONE ISTITUTO NAZIONALE DI GENETICA MOLECOLARE INGM Italy EU contribution € 1 349 100,00 Address VIA FRANCESCO SFORZA 35 20122 Milano See on map Region Nord-Ovest Lombardia Milano Activity type Research Organisations Administrative Contact Stefano Apollonio (Mr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
