title: Interleukin-7 inhibits tumor-induced CD27-CD28- suppressor T cells: implications for cancer immunotherapy.
abstract: OBJECTIVE
  We have previously reported that many types of tumors can induce changes in human T cells that lead to the acquisition of suppressive function and phenotypic alterations resembling those found in senescent T cells. In the present study, we find a role for interleukin 7 (IL-7) in protecting T cells from these changes and further define involved signaling pathways.
  
  
  METHODS
  We evaluated the ability of IL-7 treatment to prevent the gain of suppressive function and phenotypic alterations in human T cells after a short coculture with tumor cells in vitro. We then used inhibitors of components of the phosphoinositide 3-kinase (PI3K)/AKT pathway and short interfering RNA knockdown of Mcl-1 and Bim to evaluate the role of these signaling pathways in IL-7 protection.
  
  
  RESULTS
  We found that IL-7 inhibits CD27/CD28 loss and maintains proliferative capacity, IL-2 production, and reduced suppressive function. The protective ability of IL-7 depended on activation of the PI3K/AKT pathway, which inhibited activation of glycogen synthase kinase 3β, which, in turn, prevented the phosphorylation and loss of Mcl-1. We further showed a key role for Mcl-1 in that its knockdown or inhibition abrogated the effects of IL-7. In addition, knockdown of the Mcl-1 binding partner and proapoptotic protein Bim protected T cells from these dysfunctional alterations.
  
  
  CONCLUSIONS
  These observations confirm the role for Bcl-2 family members in cytokine signaling and suggest that IL-7 treatment in combination with other immunotherapies could lead to new clinical strategies to maintain normal T-cell function and reduce tumor-induced generation of dysfunctional and suppressor T cells.
authors.affiliation: Institutes of Head and Neck, Dermatology and Plastic Surgery, Taussig Cancer Center and Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lukas W
authors.initials: LW
authors.lastname: Pfannenstiel
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Bolesta
authors.forename: Carolina L
authors.initials: CL
authors.lastname: Montes
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Chapoval
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Gartenhaus
authors.forename: Scott E
authors.initials: SE
authors.lastname: Strome
authors.forename: Brian R
authors.initials: BR
authors.lastname: Gastman
mesh_terms: D018106:CD28 Antigens / Q000378:metabolism*; D045744:Cell Line, Tumor; D019254:Genes, bcl-2; D006801:Humans; D015851:Interleukin-7 / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009369:Neoplasms / Q000276:immunology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism*
chemical_list: D018106:CD28 Antigens; D015851:Interleukin-7; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D019869:Phosphatidylinositol 3-Kinases; C523442:PIK3R3 protein, human; D051058:Oncogene Protein v-akt