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and STAT3 during Hypoxia Induced an Impairment of Tumor Susceptibility to CTL-Mediated Cell Lysis1,2
* Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 753, Villejuif, France;
Department of Hepatology, University Hospital Gasthuisberg, Leuven, Belgium;
Institut Gustave Roussy PR2, Villejuif, France;
INSERM, Unité Mixte de Recherche (UMR) 542, Université de Paris XI, Hôpital Paul Brousse, Villejuif, France;
¶ Institute of Signalling, Developmental Biology and Cancer Research, Centre National de la Recherche Scientifique UMR 6543, Nice, France; and
|| Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne, Switzerland
Hypoxia is an essential component of tumor microenvironment. In this study, we investigated the influence of hypoxia (1% PO2) 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-1
(HIF-1) 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-1 and phospho-STAT3 was observed. Interestingly, gene silencing of STAT3 by small interfering RNA resulted in HIF-1 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-1 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 phopho-STAT3 and HIF-1 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-1 in the tumor microenvironment, their targeting may represent novel strategies for immunotherapeutic intervention.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by grants from Institut National de la Santé et de la Recherche Médicale, Association pour la Recherche sur le Cancer (ARC) (no. 3272), and Ligue contre le Cancer (comité de Seine Saint-Denis), as well as Institut National du Cancer (INCA), ARC/INCA, and Agence Nationale de la Recherche.
2 Microarray Data deposition: The detailed microarray data related to this paper have been submitted to the Array Express data repository at the European Bioinformatics Institute (www.ebi.ac.uk/arrayexpress; accession no. E-TABM-611).
3 Address correspondance and reprint request to Dr. Salem Chouaib, Institut National de la Santé et de la Recherche Médicale Unité 753, Institut Gustave Roussy, 39 rue Camille Desmoulins, F-94805 Villejuif, France. E-mail address: chouaib{at}igr.fr
4 Abbreviations used in this paper: HIF-1, hypoxia-inducible factor-1; CCB-I, cucurbitacin-I; MHC-I, MHC class I; NSCLC, non-small cell lung cancer; p-STAT3, phospho-STAT3; PKB (also called AKT), protein kinase B; RNAi, RNA interference; siRNA, small interfering RNA; VEGF, vascular endothelial growth factor.
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