title: Cyclosporine A immunosuppression drives catastrophic squamous cell carcinoma through IL-22.
abstract: Immune-suppressed organ transplant recipients (OTRs) can develop catastrophic squamous cell carcinoma (SCC), characterized by multiple primary tumors, extensive body surface area involvement, or metastases. There are currently no curative systemic therapies available. We previously showed that IL-22 enhances SCC proliferation. Herein, we examined links between cyclosporine (CSA), IL-22, and SCC in patients, cell lines, and mice with UV light-induced SCC. Eighteen of 114 OTRs developed catastrophic SCC, which was strongly associated with CSA treatment. We found that CSA drives T cell polarization toward IL-22-producing T22 cells, and CSA treatment increased IL-22 receptor in SCC cells. SCC tissue from OTRs showed increased expression of IL-22RA1. CSA potentiated rescue by IL-22 of serum-starved SCC cells; treatment of SCC cells with IL-22 and CSA increased both their migratory and invasive capacity. In a UV-induced model of SCC in SKH-1 immunocompetent mice, treatment with anti-IL-22 antibody reduced tumor number and tumor burden. We found that catastrophic SCC in OTRs is associated with CSA use, which may be acting by favoring T22 polarization. Since anti-IL-22 antibody administration decreased tumor number and tumor burden in vivo, blockade of the IL-22 axis may be developed as a viable therapeutic option for catastrophic SCC.
authors.affiliation: Ronald O. Perelman Department of Dermatology, New York University (NYU) Langone Medical Center, New York, New York, USA.
authors.forename: Melody
authors.initials: M
authors.lastname: Abikhair
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, New York, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsui
authors.affiliation: Ronald O. Perelman Department of Dermatology, New York University (NYU) Langone Medical Center, New York, New York, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Yanofsky
authors.affiliation: Ronald O. Perelman Department of Dermatology, New York University (NYU) Langone Medical Center, New York, New York, USA.
authors.forename: Nazanin
authors.initials: N
authors.lastname: Roudiani
authors.affiliation: Institute for Pediatric Urology, Department of Urology, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Channa
authors.initials: C
authors.lastname: Ovits
authors.affiliation: Ronald O. Perelman Department of Dermatology, New York University (NYU) Langone Medical Center, New York, New York, USA.
authors.forename: Teddy
authors.initials: T
authors.lastname: Bryan
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Oberyszyn
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Tober
authors.affiliation: Translational Immunomonitoring Resource Center, Rockefeller University, New York, New York, USA.
authors.forename: Juana
authors.initials: J
authors.lastname: Gonzalez
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, New York, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
authors.affiliation: Institute for Pediatric Urology, Department of Urology, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Felsen
authors.affiliation: Ronald O. Perelman Department of Dermatology, New York University (NYU) Langone Medical Center, New York, New York, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Carucci
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced*; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007378:Interleukins / Q000378:metabolism*; D051379:Mice; D018123:Receptors, Interleukin / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced*; D000097043:Interleukin-22
chemical_list: D016572:Cyclosporine; D007166:Immunosuppressive Agents; D007378:Interleukins; D018123:Receptors, Interleukin; D000097043:Interleukin-22; C415369:interleukin-22 receptor