T cells stimulated by CD40L positive leukemic blasts-pulsed dendritic cells meet optimal functional requirements for adoptive T-cell therapy.
Adoptive T-cell immunotherapy may provide complementary therapy for childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In this study, we have analyzed the functional characteristics of anti-BCP-ALL effector T cells generated by co-culturing T lymphocytes and dendritic cells (DC) from allogeneic human stem cell transplantation (HSCT) donors. After 21-day co-culture with DC pulsed with CD40L+ apoptotic BCP-ALL blasts, T cells presented with both effector and central memory phenotype, and showed high and specific cytotoxic activity against leukemic cells (average lysis = 77%), mostly mediated by CD8+ T cells. Noticeably, growth of CD4 T cells was maintained (45% of total cells), which actively produced Th1 cytokines (IFN-gamma, TNF-alpha, IL-2), but not IL-4, IL-5 and IL-10. Anti-BCP-ALL T cells expressed CD49d and CXCR4 (implicated in the recruitment to bone marrow), and CD62L and CCR7 (involved in the migration to lymphoid organs). In accordance with this profile, T cells significantly migrated in response to the chemokines CXCL12 and CCL19. In conclusion, stimulation of T cells with CD40L+BCP-ALL cells-loaded DC not only elicited the generation of potent and specific anti-leukemic cytotoxic effectors, but also the differentiation of specific and functional Th-1 CD4 lymphocytes. These effectors are fully equipped to reach leukemia-infiltrated tissues and have characteristics to support and orchestrate the anti-tumor immune-response.
D'Amico
G
G
Centro Ricerca M. Tettamanti, Clinica Pediatrica Università Milano-Bicocca, Ospedale San Gerardo, Monza, Italy. giovanna.damico@pediatriamonza.it
Bonamino
M
M
Dander
E
E
Marin
V
V
Basso
G
G
Balduzzi
A
A
Biagi
E
E
Biondi
A
A
D019264:Adoptive Transfer / Q000379:methods*; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology; D023201:CD40 Ligand / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000628:therapy*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D023201:CD40 Ligand