Journal
BLOOD
Volume 126, Issue 26, Pages 2882-2891Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-06-654780
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Funding
- Bloodwise (Leukaemia and Lymphoma Research)
- Olivia Hodson Cancer fund
- Great Ormond Street Hospital Children's Charity
- National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital
- National Institute for Health Research [RP-2014-05-007, NIHR-RP-R3-12-001] Funding Source: researchfish
- National Institutes of Health Research (NIHR) [NIHR-RP-R3-12-001] Funding Source: National Institutes of Health Research (NIHR)
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Unrelated cord blood transplantation (CBT) without in vivo T-cell depletion is increasingly used to treat high-risk hematologic malignancies. Following T-replete CBT, naive CBT 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 CBT cells in mediating graft-versustumor 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 PBT 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.
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