1. Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia.
- Author
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Baginska, Joanna, Viry, Elodie, Berchem, Guy, Poli, Aurélie, Noman, Muhammad Zaeem, van Moer, Kris, Medves, Sandrine, Zimmer, Jacques, Oudin, Anaïs, Niclou, Simone P., Bleackley, R. Chris, Ing Swie Goping, Chouaib, Salem, and Janji, Bassam
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AUTOPHAGY , *NATURAL immunity , *GRANZYMES , *INTERLEUKIN-12 , *KILLER cells , *PATHOPHYSIOLOGY of anoxemia , *CELLULAR immunity , *GENETICS , *PHYSIOLOGY - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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