title: The Ovarian Cancer Chemokine Landscape Is Conducive to Homing of Vaccine-Primed and CD3/CD28-Costimulated T Cells Prepared for Adoptive Therapy.
abstract: OBJECTIVE
  Chemokines are implicated in T-cell trafficking. We mapped the chemokine landscape in advanced stage ovarian cancer and characterized the expression of cognate receptors in autologous dendritic cell (DC)-vaccine primed T cells in the context of cell-based immunotherapy.
  
  
  METHODS
  The expression of all known human chemokines in patients with primary ovarian cancer was analyzed on two independent microarray datasets and validated on tissue microarray. Peripheral blood T cells from five HLA-A2 patients with recurrent ovarian cancer, who previously received autologous tumor DC vaccine, underwent CD3/CD28 costimulation and expansion ex vivo. Tumor-specific T cells were identified by HER2/neu pentamer staining and were evaluated for the expression and functionality of chemokine receptors important for homing to ovarian cancer.
  
  
  RESULTS
  The chemokine landscape of ovarian cancer is heterogeneous with high expression of known lymphocyte-recruiting chemokines (CCL2, CCL4, and CCL5) in tumors with intraepithelial T cells, whereas CXCL10, CXCL12, and CXCL16 are expressed quasi-universally, including in tumors lacking tumor-infiltrating T cells. DC-vaccine primed T cells were found to express the cognate receptors for the above chemokines. Ex vivo CD3/CD28 costimulation and expansion of vaccine-primed Tcells upregulated CXCR3 and CXCR4, and enhanced their migration toward universally expressed chemokines in ovarian cancer.
  
  
  CONCLUSIONS
  DC-primed tumor-specific T cells are armed with the appropriate receptors to migrate toward universal ovarian cancer chemokines, and these receptors are further upregulated by ex vivo CD3/CD28 costimulation, which render T cells more fit for migrating toward these chemokines. Clin Cancer Res; 21(12); 2840-50. ©2015 AACR.
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York. Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Emese
authors.initials: E
authors.lastname: Zsiros
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Duttagupta
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania. Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: Denarda
authors.initials: D
authors.lastname: Dangaj
authors.affiliation: Department of Epidemiology & Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Hongzhe
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Renee
authors.initials: R
authors.lastname: Frank
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Thomas
authors.initials: T
authors.lastname: Garrabrant
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Hagemann
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: National Institutes of Health, Bethesda, Maryland. Sidra Medical and Research Centre, Doha, Qatar.
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.affiliation: National Institutes of Health, Bethesda, Maryland. Sidra Medical and Research Centre, Doha, Qatar.
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.affiliation: National Institutes of Health, Bethesda, Maryland. Sidra Medical and Research Centre, Doha, Qatar.
authors.forename: Davide
authors.initials: D
authors.lastname: Bedognetti
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Powell
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Janos
authors.initials: J
authors.lastname: Tanyi
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania. Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland. Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland.
authors.forename: Lana E
authors.initials: LE
authors.lastname: Kandalaft
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania. Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland. Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland. george.coukos@chuv.ch.
authors.forename: George
authors.initials: G
authors.lastname: Coukos
mesh_terms: D015415:Biomarkers; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology*; D018925:Chemokines / Q000235:genetics* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D016000:Cluster Analysis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D018106:CD28 Antigens; D017252:CD3 Complex; D019496:Cancer Vaccines; D018925:Chemokines