CD40 activation of BCP-ALL cells generates IL-10-producing, IL-12-defective APCs that induce allogeneic T-cell anergy.
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-gamma (IFN-gamma)-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.
Centro Ricerca M. Tettamanti, Clinica Pediatrica Università Milano-Bicocca, Ospedale San Gerardo, Monza (MI), Italy.
Giovanna
G
D'Amico
Marisa
M
Vulcano
Cristina
C
Bugarin
Giancarlo
G
Bianchi
Gisella
G
Pirovano
Martin
M
Bonamino
Virna
V
Marin
Paola
P
Allavena
Ettore
E
Biagi
Andrea
A
Biondi
D000938:Antigen-Presenting Cells / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D002648:Child; D017635:Clonal Anergy / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology*; D018664:Interleukin-12 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology*; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; C515370:CCR7 protein, human; D019013:CD40 Antigens; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D016753:Interleukin-10; D018664:Interleukin-12