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From the Services de Pneumologie et de Réanimation
Respiratoire,*
d’Histologie et Biologie
Tumorale,
and d’Anatomie
Pathologique,¶
Assistance Publique des hopitaux de
Paris, Hôpital Tenon, Paris; the Laboratoire de Biologie
Cellulaire et d’Immunopathologie Pulmonaire,
Université Paris VI, Unité de formation et de Recherche
Saint-Antoine; and the Unité Inserm 408,
Université Paris VII, Bichat, Paris, France
We evaluated the role of the tumor environment in the regulation of
apoptosis of tumor-infiltrating neutrophils, the number of
which correlates negatively with outcome, in patients with
adenocarcinoma of the bronchioloalveolar (BAC) subtype. We examined
three different parameters of apoptosis, namely morphological
aspect, annexin-V expression, and DNA fragmentation.
Bronchoalveolar lavage fluid (BALF) supernatants from patients with BAC
significantly inhibited the 24-hour spontaneous apoptosis of normal
peripheral blood neutrophils in vitro compared to BALF
supernatants from control patients (64 ± 4%
versus 90 ± 2% measured by annexin-V flow
cytometry, P = 0.04). The alveolar
neutrophil count correlated positively with the granulocyte
colony-stimulating factor (G-CSF) and granulocyte-macrophage
colony-stimulating factor (GM-CSF) concentrations in the patient’s
BALF. Furthermore, neutralizing antibodies (Abs) against GM-CSF
and G-CSF significantly inhibited BALF anti-apoptotic activity (15 to
40% and 34 to 63% inhibition, respectively), whereas
neutralizing Abs against interleukin (IL)-8, IL-6,
IL-1ß and tumor necrosis factor-
had no significant effect. In an
attempt to identify the cell origin of anti-apoptotic
cytokines, we tested in vitro the effect of BAC
cells (A549 cell line and primary culture derived from a patient’s BAC
tumor) on the apoptosis of peripheral blood neutrophils. Cell-free
supernatants from tumor cells did not inhibit neutrophil apoptosis. In
contrast, cell-free supernatants from tumor cells previously
exposed to conditioned media from peripheral blood mononuclear cells
and alveolar macrophages significantly inhibited spontaneous neutrophil
apoptosis. This inhibition was partially lifted when conditioned media
from mononuclear cells were previously treated with Abs against IL-1ß
and tumor necrosis factor-. As in vivo,
neutralizing Abs against GM-CSF significantly inhibited the
anti-apoptotic activity of cell culture supernatants, and
combination with Abs against G-CSF had an additive effect. In
vivo, GM-CSF and G-CSF were strongly expressed by tumor
cells and moderately or not expressed by the normal epithelium,
as assessed by immunohistochemical studies. These findings demonstrate
that the tumor environment generates local conditions that prolong
alveolar neutrophil survival through the production of soluble
factors, thereby contributing to the persistence of the
neutrophil alveolitis observed in BAC.
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