期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 43, 页码 17450-17455出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1304790110
关键词
hypoxic tumor microenvironment; innate immunity; breast adenocarcinoma; immunotherapy
资金
- Public Research Center for Health, Luxembourg [REC-LHCE-2009-0201]
- Fondation Cancer, Luxembourg [FC/2012/02]
- Ligue Contre le Cancer (Comite de Val de Marne)
- Institut National du Cancer [10128]
- Association de Recherche sur le Cancer [R01354]
- Canadian Institutes of Health Research
- Aide a la Formation-Recherche (AFR) from the Fonds National de la Recherche, Luxembourg [2009-1201]
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.
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