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Blood, 1 August 2004, Vol. 104, No. 3, pp. 744-751.
Prepublished online as a Blood First Edition Paper on March 4, 2004; DOI 10.1182/blood-2003-11-3762.
Submitted November 4, 2003
Accepted February 24, 2004
Activation of BCP-ALL cells through CD40 generates IL-10 producing, IL-12 defective APC inducing allogeneic T-cell anergy
Giovanna D'Amico, Marisa Vulcano, Cristina Bugarin, Giancarlo Bianchi, Gisella Pirovano, Martin Bonamino, Virna Marin, Paola Allavena, Ettore Biagi, and Andrea Biondi*
M.Tettamanti Research Center, Pediatric Clinic University of Milan Bicocca, San Gerardo Hospital, Monza, Italy
Immunology, Istituto Mario Negri, Milan, Italy
* Corresponding author; email: fondazione.tettamanti{at}hsgerardo.org.
The use of leukemia cells as Antigen Presenting Cells (APC) in immunotherapy is critically dependent on their capacity to initiate and sustain an anti-tumor specific immune response. Previous studies suggested that pediatric B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) can 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. Engagement of CD40 induced up-regulation of CCR7 in 7/11 cases, followed by migration to CCL19 in 2/5 cases. As accessory cells, CD40L-activated BCP-ALL induced a strong proliferative 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 IL-10, but were unable to produce bioactive IL-12 and to polarize Th1 effectors. Interestingly, addition of exogenous IL-12 induced the generation of IFN- secreting Th1 effectors and reverted the anergic profile in a secondary response. Therefore, engagement of CD40 on BCP-ALL cells is not sufficient to acquire the full functional properties of immunostimulatory APC. These results suggests caution against the potential use of CD40L-activated BCP-ALL cells as agent for immunotherapy, unless additional stimuli, such as IL-12, are provided.
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