title: Effector Antitumor and Regulatory T Cell Responses Influence the Development of Nonmelanoma Skin Cancer in Kidney Transplant Patients.
abstract: Chronic immunosuppression promotes nonmelanocytic squamous cell carcinoma (SCC) after kidney transplantation. Adaptive and innate immunity play a key role controlling tumor growth and are influenced by different immunosuppressive agents. We hypothesized that functional impairment of tumor-specific T cell responses due to calcineurin inhibitors (CNI) could contribute to SCC development, whereas conversion to mammalian target of rapamycin inhibitors (mTOR-i) could recover this protective immune response.
  
  
  
  Peripheral tumor-specific T cell responses against main SCC-derived antigens using the IFN-γ enzyme-linked immunospot assay and intratumor (IT) and circulating immune phenotypes (CD4 + T, CD8 + T, CD20 + B, CD56 + NK, FOXP3 + regulatory T [Treg] cells) were explored in a cross-sectional analysis in 59 kidney transplant patients with SCC on CNI (KT-CNI-SCC) or mTOR-i (KT-mTORi-SCC), 25 nontransplants developing SCC (NoKT-SCC) and 6 healthy controls. Moreover, 25 KT-CNI-SCC were switched to mTOR-i and evaluated after 12 months.
  
  
  
  Kidney transplant patients showed lower IT infiltrates and tumor-specific T cell responses than NoKT-SCC, and intratumoral and circulating FOXP3 + Treg cells were higher in KT-mTORi-SCC (P < 0.05). Tumor-specific T cell responses were significantly lower in KT-CNI-SCC than KT-mTORi-SCC and NoKT-SCC and predicted SCC relapses (area under the curve = 0.837; P < 0.05). One-year after mTOR-i conversion, a significant increase in FOXP3 + Treg cell numbers and tumor-specific T cell responses were observed, reaching similar levels than KT-mTORi-SCC and NoKT-SCC patients.
  
  
  
  Tumor-specific T cell responses are strongly impaired in CNI-treated patients but recover after mTOR-i conversion, reducing SCC relapses.
authors.affiliation: 1 Experimental Nephrology Laboratory, IDIBELL, Barcelona, Spain. 2 Renal Transplant Unit, Nephrology Department, Germans Trias i Pujol University Hospital, Barcelona, Spain. 3 Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, IDIBELL, Barcelona, Spain. 4 Pathology Department, Bellvitge University Hospital, IDIBELL, Barcelona, Spain. 5 Pathology Department, Germans Trias i Pujol University Hospital, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Crespo
authors.forename: Loreto
authors.initials: L
authors.lastname: Fernandez
authors.forename: Marc
authors.initials: M
authors.lastname: Lúcia
authors.forename: Edoardo
authors.initials: E
authors.lastname: Melilli
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lauzurica
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Penin
authors.forename: Ariadna
authors.initials: A
authors.lastname: Quer
authors.forename: Sergio
authors.initials: S
authors.lastname: Luque
authors.forename: Maria
authors.initials: M
authors.lastname: Quero
authors.forename: Anna
authors.initials: A
authors.lastname: Manonelles
authors.forename: Joan
authors.initials: J
authors.lastname: Torras
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Cruzado
authors.forename: Laura
authors.initials: L
authors.lastname: Cañas
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Grinyó
authors.forename: Oriol
authors.initials: O
authors.lastname: Bestard
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology*; D065095:Calcineurin Inhibitors / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D016030:Kidney Transplantation / Q000009:adverse effects*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000009:adverse effects; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016896:Treatment Outcome; D019139:Tumor Escape / Q000187:drug effects*
chemical_list: D000951:Antigens, Neoplasm; D065095:Calcineurin Inhibitors; D016207:Cytokines; D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases