CD40 activation of BCP-ALL cells generates IL-10-producing, IL-12-defective APCs that induce allogeneic T-cell anergy

Giovanna D'Amico, Marisa Vulcano, Cristina Bugarin, Giancarlo Bianchi, Gisella Pirovano, Martin Bonamino, Virna Marin, Paola Allavena, Ettore Biagi, Andrea Biondi

Research output: Contribution to journalArticlepeer-review

Abstract

The use of leukemia cells as antigen-presenting cells (APCs) in immunotherapy is critically dependent on their capacity to initiate and sustain an antitumor-specific immune response. Previous studies suggested that pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells could be manipulated in vitro through the CD40-CD40L pathway to increase their immunostimulatory capacity. We extended the APC characterization of CD40L-activated BCP-ALL for their potential use in immunotherapy in a series of 19 patients. Engaging CD40 induced the up-regulation of CCR7 in 7 of 11 patients and then the migration to CCL19 in 2 of 5 patients. As accessory cells, CD40L-activated BCP-ALL induced a strong proliferation response of naive T lymphocytes. Leukemia cells, however, were unable to sustain proliferation over time, and T cells eventually became anergic. After CD40-activation, BCP-ALL cells released substantial amounts of interleukin-10 (IL-10) but were unable to produce bioactive IL-12 or to polarize TH1 effectors. Interestingly, adding exogenous IL-12 induced the generation of interferon-γ (IFN-γ)-secreting TH1 effectors and reverted the anergic profile in a secondary response. Therefore, engaging CD40 on BCP-ALL cells is Insufficient for the acquisition of full functional properties of immunostimulatory APCs. These results suggest caution against the potential use of CD40L-activated BCP-ALL cells as agents for Immunotherapy unless additional stimuli, such as IL-12, are provided.

Original languageEnglish
Pages (from-to)744-751
Number of pages8
JournalBlood
Volume104
Issue number3
DOIs
Publication statusPublished - Aug 1 2004

ASJC Scopus subject areas

  • Hematology

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