title: Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target.
abstract: OBJECTIVE
  To define the safety and effectiveness of T cells redirected against follicle-stimulating hormone receptor (FSHR)-expressing ovarian cancer cells.
  
  
  METHODS
  FSHR expression was determined by Western blotting, immunohistochemistry, and qPCR in 77 human ovarian cancer specimens from 6 different histologic subtypes and 20 human healthy tissues. The effectiveness of human T cells targeted with full-length FSH in vivo was determined against a panel of patient-derived xenografts. Safety and effectiveness were confirmed in immunocompetent tumor-bearing mice, using constructs targeting murine FSHR and syngeneic T cells.
  
  
  RESULTS
  FSHR is expressed in gynecologic malignancies of different histologic types but not in nonovarian healthy tissues. Accordingly, T cells expressing full-length FSHR-redirected chimeric receptors mediate significant therapeutic effects (including tumor rejection) against a panel of patient-derived tumors in vivo In immunocompetent mice growing syngeneic, orthotopic, and aggressive ovarian tumors, fully murine FSHR-targeted T cells also increased survival without any measurable toxicity. Notably, chimeric receptors enhanced the ability of endogenous tumor-reactive T cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, FSHR-targeted T cells persisted as memory lymphocytes without noticeable PD-1-dependent exhaustion during end-stage disease, in the absence of tumor cell immunoediting. However, exosomes in advanced tumor ascites diverted the effector activity of this and other chimeric receptor-transduced T cells away from targeted tumor cells.
  
  
  CONCLUSIONS
  T cells redirected against FSHR+tumor cells with full-length FSH represent a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries. Clin Cancer Res; 23(2); 441-53. ©2016 AACR.
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Perales-Puchalt
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Svoronos
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Rutkowski
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Allegrezza
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Tesone
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Kyle K
authors.initials: KK
authors.lastname: Payne
authors.affiliation: Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Jayamanna
authors.initials: J
authors.lastname: Wickramasinghe
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Nguyen
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Shane W
authors.initials: SW
authors.lastname: O'Brien
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Kiranmai
authors.initials: K
authors.lastname: Gumireddy
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Qihong
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Helen F. Graham Cancer Center, Christiana Care Health System, Newark, Delaware.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Cadungog
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Denise C
authors.initials: DC
authors.lastname: Connolly
authors.affiliation: Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Julia
authors.initials: J
authors.lastname: Tchou
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania. jrconejo@Wistar.org.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Conejo-Garcia
mesh_terms: D000818:Animals; D001201:Ascites / Q000276:immunology / Q000473:pathology; D055354:Exosomes / Q000276:immunology / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D051379:Mice; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011962:Receptors, FSH / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011948:Receptors, Antigen, T-Cell; D011962:Receptors, FSH