title: Cyclosporine A Inhibits the T-bet-Dependent Antitumor Response of CD8(+) T Cells.
abstract: Transplant recipients face an increased risk of cancer compared with the healthy population. Although several studies have examined the direct effects of immunosuppressive drugs on cancer cells, little is known about the interactions between pharmacological immunosuppression and cancer immunosurveillance. We investigated the different effects of rapamycin (Rapa) versus cyclosporine A (CsA) on tumor-reactive CD8(+) T cells. After adoptive transfer of CD8(+) T cell receptor-transgenic OTI T cells, recipient mice received either skin grafts expressing ovalbumin (OVA) or OVA-expressing B16F10 melanoma cells. Animals were treated daily with Rapa or CsA. Skin graft rejection and tumor growth as well as molecular and cellular analyses of skin- and tumor-infiltrating lymphocytes were performed. Both Rapa and CsA were equally efficient in prolonging skin graft survival when applied at clinically relevant doses. In contrast to Rapa-treated animals, CsA led to accelerated tumor growth in the presence of adoptively transferred tumor-reactive CD8(+) OTI T cells. Further analyses showed that T-bet was downregulated by CsA (but not Rapa) in CD8(+) T cells and that cancer cytotoxicity was profoundly inhibited in the absence of T-bet. CsA reduces T-bet-dependent cancer immunosurveillance by CD8(+) T cells. This may contribute to the increased cancer risk in transplant recipients receiving calcineurin inhibitors.
authors: Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.|Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Fundació Clínic - IDIBAPS, Barcelona, Spain.
authors: J
authors: J
authors: Rovira
authors: Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
authors: P
authors: P
authors: Renner
authors: Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
authors: M
authors: M
authors: Sabet-Baktach
authors: Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
authors: E
authors: E
authors: Eggenhofer
authors: Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
authors: G E
authors: GE
authors: Koehl
authors: Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
authors: M
authors: M
authors: Lantow
authors: Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
authors: S A
authors: SA
authors: Lang
authors: Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
authors: H J
authors: HJ
authors: Schlitt
authors: Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Fundació Clínic - IDIBAPS, Barcelona, Spain.|Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.
authors: J M
authors: JM
authors: Campistol
authors: Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
authors: E K
authors: EK
authors: Geissler
authors: Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.|MedStar Georgetown Transplant Institute, Georgetown University Hospital, Washington, DC.
authors: A
authors: A
authors: Kroemer
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020123:Sirolimus / Q000494:pharmacology; D016038:Skin Transplantation; D020825:T-Box Domain Proteins / Q000502:physiology*; D000098815:T-bet Transcription Factor
chemical_list: D007166:Immunosuppressive Agents; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D016572:Cyclosporine; D020123:Sirolimus
keywords: animal models: murine; basic (laboratory) research/science; cancer/malignancy/neoplasia; cyclosporine A (CsA); immunosuppressant; immunosuppressant; calcineurin inhibitor; immunosuppression/immune modulation; mechanistic target of rapamycin (mTOR); organ transplantation in general; rejection