Augmentation of antitumor immune responses after adoptive transfer of bone marrow derived from donors immunized with tumor lysate-pulsed dendritic cells.
We demonstrated previously that tumor lysate-pulsed dendritic cells (TP-DC) could mediate a specific and long-lasting antitumor immune response against a weakly immunogenic breast tumor during early lymphoid reconstitution. The purpose of this study was to examine the potential therapeutic efficacy of bone marrow transplants from TP-DC-vaccinated donors. In 2 aggressive metastatic models, bone marrow transplantation with donor bone marrow cells from TP-DC-immunized mice mediated a tumor-specific immune response in the recipient, and this caused regressions of preexisting tumor metastases. After vaccination with TP-DC, donors harbored increased numbers of both activated CD4+ and CD8+ T-cell populations in the bone marrow. Adoptive transfer of T cells purified from the bone marrow of TP-DC-vaccinated mice led to a reduction in preestablished lung metastases, whereas depletion of T cells from bone marrow abolished this effect. By using T cells derived from the bone marrow of TP-DC-vaccinated major histocompatibility complex class I and class II knockout mice, the effector cells required for the observed antitumor effect were determined to be major histocompatibility complex class I-restricted CD8+ T cells. Additionally, the tumor burden in TP-DC-immunized transplant recipients could be reduced further by repetitive TP-DC immunizations after bone marrow transplantation. Collectively, these results demonstrate an important therapeutic role of bone marrow from TP-DC-immunized donors and raise the potential for this approach in patients with advanced cancer.
Department of Surgery and Tumor Immunology and Immunotherapy Program of the Comprehensive Cancer Center and Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, Michigan, USA.
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W
Asavaroengchai
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Kotera
N
N
Koike
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S
Pilon-Thomas
J J
JJ
Mulé
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000951:Antigens, Neoplasm / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000379:methods; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D005260:Female; D005434:Flow Cytometry; D005805:Genes, MHC Class I / Q000235:genetics / Q000276:immunology; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014611:Vaccination
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D007371:Interferon-gamma