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

  • Tumor Immunotherapy and Microenvironment
  • NORLUX Neuro-Oncology Laboratory
October 22, 2013 By:
  • Baginska J
  • Viry E
  • Berchem G
  • Poli A
  • Noman MZ
  • van Moer K
  • Medves S
  • Zimmer J
  • Oudin A
  • Niclou SP
  • Bleackley RC
  • Goping IS
  • Chouaib S
  • Janji B.

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.

2013 Oct. Proc Natl Acad Sci U S A.110(43):17450-5. Epub 2013 Oct 7.
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