Title: The cooperative induction of hypoxia-inducible factor-1 alpha and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis
Authors: Noman, Muhammad Zaeem ×
Buart, Stéphanie
van Pelt, Jos
Richon, Catherine
Hasmim, Meriem
Leleu, Nathalie
Suchorska, Wictoria Maria
Jalil, Abdelali
Lecluse, Yann
El Hage, Faten
Giuliani, Massimo
Pichon, Christophe
Azzarone, Bruno
Mazure, Nathalie
Romero, Pedro
Mami-Chouaib, Fathia
Chouaib, Salem #
Issue Date: Mar-2009
Publisher: American Association of Immunologists
Series Title: Journal of Immunology vol:182 issue:6 pages:3510-21
Abstract: Hypoxia is an essential component of tumor microenvironment. In this study, we investigated the influence of hypoxia (1% PO(2)) on CTL-mediated tumor cell lysis. We demonstrate that exposure of target tumor cells to hypoxia has an inhibitory effect on the CTL clone (Heu171)-induced autologous target cell lysis. Such inhibition correlates with hypoxia-inducible factor-1alpha (HIF-1alpha) induction but is not associated with an alteration of CTL reactivity as revealed by granzyme B polarization or morphological change. Western blot analysis indicates that although hypoxia had no effect on p53 accumulation, it induced the phosphorylation of STAT3 in tumor cells by a mechanism at least in part involving vascular endothelial growth factor secretion. We additionally show that a simultaneous nuclear translocation of HIF-1alpha and phospho-STAT3 was observed. Interestingly, gene silencing of STAT3 by small interfering RNA resulted in HIF-1alpha inhibition and a significant restoration of target cell susceptibility to CTL-induced killing under hypoxic conditions by a mechanism involving at least in part down-regulation of AKT phosphorylation. Moreover, knockdown of HIF-1alpha resulted in the restoration of target cell lysis under hypoxic conditions. This was further supported by DNA microarray analysis where STAT3 inhibition resulted in a partly reversal of the hypoxia-induced gene expression profile. The present study demonstrates that the concomitant hypoxic induction of phospho-STAT3 and HIF-1alpha are functionally linked to the alteration of non-small cell lung carcinoma target susceptibility to CTL-mediated killing. Considering the eminent functions of STAT3 and HIF-1alpha in the tumor microenvironment, their targeting may represent novel strategies for immunotherapeutic intervention.
ISSN: 0022-1767
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Hepatology
× corresponding author
# (joint) last author

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