title: T Cells Derived From Human Melanoma Draining Lymph Nodes Mediate Melanoma-specific Antitumor Responses In Vitro and In Vivo in Human Melanoma Xenograft Model.
abstract: It has been established in murine models that lymph nodes draining a progressively growing tumor contain antigen-specific T cells capable of mediating protective immune responses upon adoptive transfer. However, naturally occurring human tumor-draining lymph nodes (TDLNs) have yet to be fully investigated. In this study, we analyzed TDLNs from patients with stage III melanoma who were undergoing routine lymph node dissection. Following short-term (14 d) culture activation with anti-CD3/anti-CD28 microbeads and expansion in low concentrations of IL-2, the melanoma-draining lymph node (MDLN) cells were ∼ 60% CD4-activated and ∼ 40% CD8-activated T cells. The activated MDLN cells demonstrated reactivity in response to overlapping peptides spanning the sequence of 4 different known melanoma antigens MAGEA1, Melan-A/MART-1, NY-ESO-1, and Prame/OIP4, suggesting the presence of melanoma-specific T cells. Coculture of activated MDLN T cells with cancer cells in vitro resulted in preferential apoptosis of human cancer cell lines that were cocultured with T cells with high degree of MHC matching. Adoptive transfer of MDLN T cells with high degree of MHC matching to A375 to mice-bearing human A375 melanoma xenografts resulted in dose-dependent improvement in survival. Although prior human studies have demonstrated the immune responses within melanoma vaccine-draining lymph nodes, this study presents evidence for the first time that naturally occurring human MDLN samples contain melanoma-experienced CD4 and CD8 T cells that can be readily cultured and expanded to mediate protective immune responses both in vitro and in vivo in a human melanoma xenograft model.
authors.affiliation: *Department of Biomedical Engineering, Case Western Reserve University †Case Comprehensive Cancer Center ‡Seidman Cancer Center §Division of Surgical Oncology, University Hospitals Case Medical Center, Cleveland, OH.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.forename: Hallie
authors.initials: H
authors.lastname: Graor
authors.forename: Anthony
authors.initials: A
authors.lastname: Visioni
authors.forename: Madeleine
authors.initials: M
authors.lastname: Strohl
authors.forename: Lu
authors.initials: L
authors.lastname: Yan
authors.forename: Kevin
authors.initials: K
authors.lastname: Caja
authors.forename: Julian A
authors.initials: JA
authors.lastname: Kim
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D019496:Cancer Vaccines / Q000008:administration & dosage*; D063646:Carcinogenesis; D002478:Cells, Cultured; D018920:Coculture Techniques; D064593:Heterografts; D006648:Histocompatibility; D006801:Humans; D066298:In Vitro Techniques; D008198:Lymph Nodes / Q000276:immunology*; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D058950:Melanoma-Specific Antigens / Q000276:immunology; D009367:Neoplasm Staging; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation
chemical_list: D019496:Cancer Vaccines; D058950:Melanoma-Specific Antigens