Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non–Small Cell Lung Cancer

Abstract

CD47-specific antibodies and fusion proteins that block CD47-SIRPa signaling are employed as antitumor agents for several cancers. Here, we investigated the synergistic antitumor effect of simultaneously targeting CD47 and autophagy in nonsmall cell lung cancer (NSCLC). SIRPaD1-Fc, a novel CD47-targeting fusion protein, was generated and was found to increase the phagocytic and cytotoxic activities of macrophages against NSCLC cells. During this process, autophagy was markedly triggered, which was characterized by the three main stages of autophagic flux, including formation and accumulation of autophagosomes, fusion of autophagosomes with lysosomes, and degradation of autophagosomes in lysosomes. Meanwhile, reactive oxygen species and inactivation of mTOR were shown to be involved in autophagy initiation in SIRPaD1-Fc-treated cells, indicating a probable mechanism for autophagy activation after targeting CD47 by SIRPaD1-Fc. Inhibition of autophagy enhanced macrophage-mediated phagocytosis and cytotoxicity against SIRPaD1-Fc-treated NSCLC cells. In addition, simultaneously targeting both CD47 and autophagy in NSCLC xenograft models elicited enhanced antitumor effects, with recruitment of macrophages, activated caspase-3, and overproduction of ROS at the tumor site. Our data elucidated the cytoprotective role of autophagy in CD47-targeted therapy and highlighted the potential approach for NSCLC treatment by simultaneously targeting CD47 and autophagy.

Autophagy suppression potentiates the anti-glioblastoma effect of asparaginase in vitro and in vivo

“…Depending on cell type and stimulus, autophagy could be a double-edged sword in cancer treatment—chemotherapeutics could either initiate cytoprotective autophagy or induce autophagic tumor cell death [ 21 , 26 , 28 , 29 , 41 , 42 , 43 ]. Most of the time, especially in amino acid deprivation therapy, autophagy could degrade superfluous or dysfunctional proteins and organelles to supply nutrients and materials for dying tumor cells, thus served as protective mechanism [ 21 , 26 , 28 , 29 ].…”

Autophagy Modulation in Cancer: Current Knowledge on Action and Therapy

“…It was found that EB1089 induces a novel cytostatic form of autophagy suppressing NSCLC proliferation [ 166 ]. Additionally, Zhang et al have shown that simultaneous targeting of CD47 and autophagy in NSCLC xenograft models enhance antitumor activity through the activation of caspase-3, recruitment of macrophages, and overproduction of ROS [ 167 ].…”

Emerging immunotherapy targets in lung cancer

“…[ 77 ] A CD47-targeting fusion protein SIRPα-Fc was reported to activate macrophages in NSCLC xenograft mice, probably mediated by inactivation of mammalian target of rapamycin and reactive oxygen species, and was enhanced by simultaneously targeting autophagy. [ 78 ] Caspase-3/7 were poorly activated in NSCLC, [ 77 ] while caspase-3 was activated in CD47-targeting therapy, indicating an acceleration of apoptosis. [ 78 ] An anti-CD47 small interfering RNA (siRNA) was also shown to be effective in inhibiting tumor invasion and metastasis in NSCLC cell lines.…”

“…[ 78 ] Caspase-3/7 were poorly activated in NSCLC, [ 77 ] while caspase-3 was activated in CD47-targeting therapy, indicating an acceleration of apoptosis. [ 78 ] An anti-CD47 small interfering RNA (siRNA) was also shown to be effective in inhibiting tumor invasion and metastasis in NSCLC cell lines. [ 75 ] In addition, Wu et al [ 79 ] explored a novel strategy to deliver anti-CD47 siRNA to kill lung cancer cells precisely without adverse effects on CD47-expressing platelets and red blood cells, exploiting the excessive glutamine demand of tumor cells.…”