title: Induced regulatory T cells in inhibitory microenvironments created by cancer.
abstract: BACKGROUND
  Regulatory T cells (Tregs) accumulating in the peripheral circulation and tumor sites of patients contribute to tumor escape from the host immune system. Tregs encompass subsets of immune cells with distinct phenotypic and functional properties. Whereas natural (n) or thymic-derived (t) Tregs regulate responses to self-antigens, inducible (i) or peripheral (p) Tregs generated and expanded in regulatory microenvironments control immune responses to a broad variety of antigens.
  
  
  METHODS
  Tregs accumulating in the tumor microenvironment (TME) are contextually regulated. They acquire phenotypic and functional attributes imposed by the inhibitory molecular pathways operating in situ. Several molecular pathways active in human cancer are reviewed. The pathways may differ from one tumor to another, and environmentally induced Tregs may be functionally distinct. Potential therapeutic strategies for selective silencing of iTregs are considered in the light of the newly acquired understanding of their phenotypic and functional diversity.
  
  
  CONCLUSIONS
  Human Tregs accumulating in cancer comprise 'bad' subsets, which inhibit antitumor immunity, and 'good' anti-inflammatory subsets, which maintain tolerance to self and benefit the host. Future therapeutic strategies targeting Tregs will need to discriminate between these Treg subsets and will need to consider reprogramming strategies instead of Treg elimination. Re-establishment of effective antitumor immune responses in cancer patients without disturbing a normal homeostatic T-cell balance will greatly benefit from insights into inhibitory pathways engaged by human tumors.
authors.affiliation: University of Pittsburgh Cancer Institute , 5117 Centre Avenue, Pittsburgh, PA 15213 , USA +1 412 624 0096 ; +1 412 624 0264 ; whitesidetl@upmc.edu.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
mesh_terms: D006801:Humans; D007108:Immune Tolerance; D007167:Immunotherapy / Q000379:methods*; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
keywords: cancer; immune suppression; inducible regulatory T cell; inhibitory pathways; regulatory T cell-directed therapy; tumor microenvironment