title: Cord blood T cells mediate enhanced antitumor effects compared with adult peripheral blood T cells.
abstract: Unrelated cord blood transplantation (CBT) without in vivo T-cell depletion is increasingly used to treat high-risk hematologic malignancies. Following T-replete CBT, naïve CB T cells undergo rapid peripheral expansion with memory-effector differentiation. Emerging data suggest that unrelated CBT, particularly in the context of HLA mismatch and a T-replete graft, may reduce leukemic relapse. To study the role of CB T cells in mediating graft-versus-tumor responses and dissect the underlying immune mechanisms for this, we compared the ability of HLA-mismatched CB and adult peripheral blood (PB) T cells to eliminate Epstein-Barr virus (EBV)-driven human B-cell lymphoma in a xenogeneic NOD/SCID/IL2rg(null) mouse model. CB T cells mediated enhanced tumor rejection compared with equal numbers of PB T cells, leading to improved survival in the CB group (P < .0003). Comparison of CB T cells that were autologous vs allogeneic to the lymphoma demonstrated that this antitumor effect was mediated by alloreactive rather than EBV-specific T cells. Analysis of tumor-infiltrating lymphocytes demonstrated that CB T cells mediated this enhanced antitumor effect by rapid infiltration of the tumor with CCR7(+)CD8(+) T cells and prompt induction of cytotoxic CD8(+) and CD4(+) T-helper (Th1) T cells in the tumor microenvironment. In contrast, in the PB group, this antilymphoma effect is impaired because of delayed tumoral infiltration of PB T cells and a relative bias toward suppressive Th2 and T-regulatory cells. Our data suggest that, despite being naturally programmed toward tolerance, reconstituting T cells after unrelated T-replete CBT may provide superior Tc1-Th1 antitumor effects against high-risk hematologic malignancies.
authors.affiliation: Molecular and Cellular Immunology Section, University College London Institute of Child Health, London, United Kingdom; Department of Haematology and Bone Marrow transplantation, Birmingham Children's Hospital, Birmingham, United Kingdom;
authors.forename: Prashant
authors.initials: P
authors.lastname: Hiwarkar
authors.affiliation: Molecular and Cellular Immunology Section, University College London Institute of Child Health, London, United Kingdom; Department of Immunology and.
authors.forename: Waseem
authors.initials: W
authors.lastname: Qasim
authors.affiliation: Molecular and Cellular Immunology Section, University College London Institute of Child Health, London, United Kingdom;
authors.forename: Ida
authors.initials: I
authors.lastname: Ricciardelli
authors.affiliation: Laboratory Immunology, Great Ormond Street Hospital for Children, London, United Kingdom;
authors.forename: Kimberly
authors.initials: K
authors.lastname: Gilmour
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom;
authors.forename: Sergio
authors.initials: S
authors.lastname: Quezada
authors.affiliation: Anthony Nolan Research Institute, London, United Kingdom; Cancer Institute, University College London, London, United Kingdom; and.
authors.forename: Aurore
authors.initials: A
authors.lastname: Saudemont
authors.affiliation: Molecular and Cellular Immunology Section, University College London Institute of Child Health, London, United Kingdom; Department of Bone Marrow Transplantation, Great Ormond Street Hospital for Children, London, United Kingdom.
authors.forename: Persis
authors.initials: P
authors.lastname: Amrolia
authors.affiliation: Molecular and Cellular Immunology Section, University College London Institute of Child Health, London, United Kingdom; Department of Bone Marrow Transplantation, Great Ormond Street Hospital for Children, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Veys
mesh_terms: D000818:Animals; D036101:Cord Blood Stem Cell Transplantation / Q000379:methods*; D004195:Disease Models, Animal; D005312:Fetal Blood; D020350:Graft vs Tumor Effect / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays