Disrupting CD47-SIRPα axis alone or combined with autophagy depletion for the therapy of glioblastoma

CD47-targeting immune checkpoint inhibitors have been investigated for immunotherapy of several cancers, glioblastoma, one of the most common tumors in brain, was still a challenge for CD47-targeting therapy. Herein, we reported novel strategies for glioblastoma therapy via blocking CD47-signal regulatory protein-alpha (SIRP alpha) by SIRP alpha-Fc alone or in combination with autophagy inhibition. Our results showed that SIRP alpha-Fc increased macrophages-triggered cytotoxicity and phagocytosis of glioblastoma cells then elicited potent anti-tumor efficacy. During the treatment, SIRP alpha-Fc induced autophagy and autophagic flux in glioblastoma cells and Akt/mammalian target of rapamycin (mTOR) inactivation was participated in the autophagy activation. Inhibition of autophagy by pharmacological agents or small-interfering RNA increased SIRP alpha-Fc-triggered macrophage phagocytosis and cytotoxicity. Importantly, when compared with SIRP alpha-Fc treatment, blocking both CD47/SIRP alpha and autophagy significantly increased infiltration of macrophages and apoptosis of tumor cells, triggering potentiated anti-glioblastoma effect and extended median survival. Further experiments showed that adaptive immune response, including CD8(+) T-cell subsets, was also played a crucial role in SIRP alpha-Fc-induced glioblastoma rejection. Our results indicated that SIRP alpha-Fc alone or combined with autophagy inhibitors elicited potent anti-glioblastoma effect, highlighting potential therapeutic strategies of glioblastoma via blocking CD47/SIRP alpha alone or in combination with autophagy inhibitor.