399P - Blocking CD47 and autophagy for the therapy of non-small-cell lung cancer

Date 18 December 2016
Event ESMO Asia 2016 Congress
Session Poster lunch
Topics Immunotherapy
Thoracic malignancies
Presenter Xuyao Zhang
Citation Annals of Oncology (2016) 27 (suppl_9): ix123-ix125. 10.1093/annonc/mdw588
Authors X. Zhang, D. Ju
  • Department Of Microbiological And Biochemical Pharmacy, School of Pharmacy, Fudan University, 201203 - Shanghai/CN

Abstract

Background

Cluster of Differentiation (CD47), known as integrin-associated receptor protein, is over-expressed on non-small-cell lung cancer (NSCLC) cells. It can interact with signal regulatory protein-alpha (SIRPα) and inhibit macrophage phagocytosis. Autophagy, a key ingredient in microenvironment maintenance, plays a critical role in tumorigenesis, tumor development and metastasis. Here, we report a potential approach for NSCLC therapy by blocking both CD47 and autophagy.

Background

Cluster of Differentiation (CD47), known as integrin-associated receptor protein, is over-expressed on non-small-cell lung cancer (NSCLC) cells. It can interact with signal regulatory protein-alpha (SIRPα) and inhibit macrophage phagocytosis. Autophagy, a key ingredient in microenvironment maintenance, plays a critical role in tumorigenesis, tumor development and metastasis. Here, we report a potential approach for NSCLC therapy by blocking both CD47 and autophagy.

Methods

A novel fusion protein named SIRPα-Fc was prepared and employed to block CD47 on NSCLC cells. Three standard techniques including transmission electron microscope, confocal microscope and western blot were used to detect autophagy in NSCLC cells after CD47 blockade. LDH-release and CFSE staining assay were applied to detect the phagocytosis of NSCLC cells after blockade of CD47/autophagy. NSCLC xenograft models were established in BALB/c nude mice to investigate the anti-tumor effect of blocking both CD47 and autophagy in NSCLC.

Methods

A novel fusion protein named SIRPα-Fc was prepared and employed to block CD47 on NSCLC cells. Three standard techniques including transmission electron microscope, confocal microscope and western blot were used to detect autophagy in NSCLC cells after CD47 blockade. LDH-release and CFSE staining assay were applied to detect the phagocytosis of NSCLC cells after blockade of CD47/autophagy. NSCLC xenograft models were established in BALB/c nude mice to investigate the anti-tumor effect of blocking both CD47 and autophagy in NSCLC.

Results

We found that blocking CD47 could increase the phagocytosis of macrophage against NSCLC cells. During this process, autophagy was triggered, which was characterized by the three main stages of autophagic flux including: formation and accumulation of autophagosomes, fusion of autophagosomes into lysosomes and degradation of autophagosomes in lysosomes. Importantly, inhibition of autophagy in NSCLC cells could notably enhance the effect of CD47 blockade on macrophage-mediated phagocytosis, while co-suppression of autophagy and CD47 signaling could also elicit enhanced anti-NSCLC efficacy in vivo.

Results

We found that blocking CD47 could increase the phagocytosis of macrophage against NSCLC cells. During this process, autophagy was triggered, which was characterized by the three main stages of autophagic flux including: formation and accumulation of autophagosomes, fusion of autophagosomes into lysosomes and degradation of autophagosomes in lysosomes. Importantly, inhibition of autophagy in NSCLC cells could notably enhance the effect of CD47 blockade on macrophage-mediated phagocytosis, while co-suppression of autophagy and CD47 signaling could also elicit enhanced anti-NSCLC efficacy in vivo.

Conclusions

We demonstrated that autophagy was induced in NSCLC cells after CD47 blockade, while inhibition of autophagy could significantly enhance the anti-tumor efficacy of CD47 blockade in NSCLCs. Our data elucidated the critical role of autophagy in CD47 abolishment-based NSCLS therapy and highlighted the potential approach for the treatment of NSCLC by blocking autophagy and CD47.

Conclusions

We demonstrated that autophagy was induced in NSCLC cells after CD47 blockade, while inhibition of autophagy could significantly enhance the anti-tumor efficacy of CD47 blockade in NSCLC. Our data elucidated the critical role of autophagy in CD47 abolishment-based NSCLC therapy and highlighted the potential approach for the treatment of NSCLC by blocking autophagy and CD47.

Clinical trial indentification

There is no clinical trial in this study.

Legal entity responsible for the study

N/A

Funding

the National Natural Science Foundation of China (81573332)

Disclosure

All authors have declared no conflicts of interest.