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

Abstract

Significance Natural killer (NK) cells are effectors of the antitumor immunity, able to kill cancer cells through the release of the cytotoxic protease granzyme B. NK-based therapies have recently emerged as promising anticancer strategies. It is well established that hypoxic microenvironment interferes with the function of antitumor immune cells and constitutes a major obstacle for cancer immunotherapies. We showed that breast cancer cells evade effective NK-mediated killing under hypoxia by activating autophagy that we have identified to be responsible for the degradation of NK-derived granzyme B. We demonstrated that blocking autophagy restored NK-mediated lysis in vitro, and facilitated breast tumor elimination by NK cells in mice. We provided evidence that targeting autophagy may pave the way to achieve more effective NK-based anticancer immunotherapy.