The cooperative induction of hypoxia-inducible factor-1α and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis

Muhammad Zaeem Noman, Stéphanie Buart, Jos Van Pelt, Catherine Richon, Meriem Hasmim, Nathalie Leleu, Wictoria Maria Suchorska, Abdelali Jalil, Yann Lecluse, Faten El Hage, Massimo Giuliani, Christophe Pichon, Bruno Azzarone, Nathalie Mazure, Pedro Romero, Fathia Mami-Chouaib, Salem Chouaib

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Abstract

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-1α (HIF-1α) 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-1α and phospho-STAT3 was observed. Interestingly, gene silencing of STAT3 by small interfering RNA resulted in HIF-1α 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-1α 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-1α 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-1α in the tumor microenvironment, their targeting may represent novel strategies for immunotherapeutic intervention.

Original languageEnglish
Pages (from-to)3510-3521
Number of pages12
JournalJournal of Immunology
Volume182
Issue number6
DOIs
Publication statusPublished - Mar 15 2009

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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    Noman, M. Z., Buart, S., Van Pelt, J., Richon, C., Hasmim, M., Leleu, N., Suchorska, W. M., Jalil, A., Lecluse, Y., El Hage, F., Giuliani, M., Pichon, C., Azzarone, B., Mazure, N., Romero, P., Mami-Chouaib, F., & Chouaib, S. (2009). The cooperative induction of hypoxia-inducible factor-1α and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis. Journal of Immunology, 182(6), 3510-3521. https://doi.org/10.4049/jimmunol.0800854