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Immunology

T cells stimulated by CD40L positive leukemic blasts-pulsed dendritic cells meet optimal functional requirements for adoptive T-cell therapy

Leukemia volume 20, pages 2015–2024 (2006)Cite this article

Abstract

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-γ, TNF-α, 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.

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Acknowledgements

We thank Dr Dario Campana (St. Jude Children' Research Hospital, Memphis, TN) for providing us with the human bone marrow stromal cell line. The authors want to express their gratitude to Dr Paola Allavena for critical reading of this paper. This work was supported in part by grants from the Associazione Italiana Ricerca sul Cancro (AIRC), MIUR PRIN 2003 (2003 069141_005), the Fondazione ‘M Tettamanti’, the Comitato ‘S Verri’ and Fondazione Città Della Speranza (GB). V Marin is a fellow of the Vita-Salute San Raffaele University PhD program in Molecular Medicine. M Bonamino is a fellow of the Medical Biochemistry Institute program of the Universidade Federal do Rio de Janeiro and of the Instituto Nacional de Câncer (INCa), Brazil, and supported by CAPES and Fondazione ‘M Tettamanti’ scholarships.

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Authors and Affiliations

  1. Centro Ricerca ‘M. Tettamanti’, Clinica Pediatrica Università Milano-Bicocca, Ospedale San Gerardo, Monza, Italy

    G D'Amico, E Dander, V Marin, A Balduzzi, E Biagi & A Biondi

  2. Departamento de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil and Centro de Transplante de Medula Óssea, Instituto Nacional de Câncer, Rio de Janeiro, Brazil

    M Bonamino

  3. Laboratorio di Oncoematologia Pediatrica, Clinica Pediatrica Università di Padova, Padova, Italy

    G Basso

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  1. G D'Amico
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Correspondence to G D'Amico.

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D'Amico, G., Bonamino, M., Dander, E. et al. T cells stimulated by CD40L positive leukemic blasts-pulsed dendritic cells meet optimal functional requirements for adoptive T-cell therapy. Leukemia 20, 2015–2024 (2006). https://doi.org/10.1038/sj.leu.2404390

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