Interleukin-12 production by leukemia-derived dendritic cells counteracts the inhibitory effect of leukemic microenvironment on T cells

Antonio Curti, Simona Pandolfi, Michela Aluigi, Alessandro Isidori, Isabella Alessandrini, Claudia Chiodoni, Nicoletta Testoni, Mario P. Colombo, Michele Baccarani, Roberto M. Lemoli

Research output: Contribution to journalArticle

Abstract

Objective. Acute myeloid leukemia (AML) cells are poorly immunogenic and inhibit T-cell function. AML-derived dendritic cells (AML-DCs) have better antigen-presentation capacity than undifferentiated leukemic blasts, but may not be fully competent to stimulate T cells previously inhibited by leukemic cells. Materials and Methods. AML-DCs were generated from AML cells and used to stimulate proliferation and cytokine production by T cells previously inhibited by AML cells. AML-DCs were also transfected with interleukin (IL)-12 gene by the nonviral method, nucleofection. Results. Mature AML-DCs stimulated naive and, to a lesser extent, leukemic cell (LC)-cultured T cells more efficiently than their immature counterparts and their activity was mediated by IL-12. AML-DCs generated from CD14- AML samples (which represent 80% of total AML patients) were defective in IL-12 production and T-cell activation. Addition of exogenous IL-12 to LC-cultured T cells stimulated by CD14--derived AML-DCs restored optimal interferon-γ (IFN-γ) production and Th1 skewing. IL-12 gene-nucleofected AML-DCs derived from CD14- cells produced significant amounts of IL-12, maintained leukemia-specific karyotype, DC-like phenotype, and function. When stimulated by IL-12-gene transduced CD14--derived AML-DCs, LC-cultured T cells produced higher concentrations of IFN-γ, thus maintaining a Th1 cytokine profile. Conclusion. IL-12 produced by AML-DCs plays a critical role in counteracting the inhibitory activity of LCs on T-cell function. IL-12 gene can be successfully expressed into AML-DCs defective in endogenous IL-12 production by using a novel nonviral method that does not modify their phenotypical, cytogenetic, and functional features. Genetically modified AML-DCs restore a near normal T-cell function.

Original languageEnglish
Pages (from-to)1521-1530
Number of pages10
JournalExperimental Hematology
Volume33
Issue number12
DOIs
Publication statusPublished - Dec 2005

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ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

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