Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia

Joanna Baginska, Elodie Viry, Guy Berchem, Aurélie Poli, Muhammad Zaeem Noman, Kris Van Moer, Sandrine Medves, Jacques Zimmer, Anaïs Oudin, Simone P. Niclou, R. Chris Bleackley, Ing Swie Goping, Salem Chouaib, Bassam Janji*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

191 Citations (Scopus)

Abstract

Recent studies demonstrated that autophagy is an important regulator of innate immune response. However, the mechanism by which autophagy regulates natural killer (NK) cell-mediated antitumor immune responses remains elusive. Here,we demonstrate that hypoxia impairs breast cancer cell susceptibility to NK-mediated lysis in vitro via the activation of autophagy. This impairment was not related to a defect in target cell recognition by NK cells but to the degradation of NK-derived granzyme B in autophagosomes of hypoxic cells. Inhibition of autophagy by targeting beclin1 (BECN1) restored granzyme B levels in hypoxic cells in vitro and induced tumor regression in vivo by facilitating NK-mediated tumor cell killing. Together, our data highlight autophagy as a mechanism underlying the resistance of hypoxic tumor cells to NK-mediated lysis. The work presented here provides a cutting-edge advance in our understanding of the mechanism by which hypoxia-induced autophagy impairs NK-mediated lysis in vitro and paves the way for the formulation of more effective NK cell-based antitumor therapies.

Original languageEnglish
Pages (from-to)17450-17455
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number43
DOIs
Publication statusPublished - 22 Oct 2013

Keywords

  • Breast adenocarcinoma
  • Hypoxic tumor microenvironment
  • Immunotherapy
  • Innate immunity

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