12PD - Novel and promising therapeutic approaches for glioblastoma: blocking CD47-SIRP_ axis alone or combined with autophagy depletion (12PD)

Date 09 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Poster Discussion session
Topics Anti-Cancer Agents & Biologic Therapy
Non-Small-Cell Lung Cancer, Metastatic
Cancer Immunology and Immunotherapy
Lung and other Thoracic Tumours
Presenter Xuyao Zhang
Citation Annals of Oncology (2017) 28 (suppl_11): xi3-xi5. 10.1093/annonc/mdx710
Authors X. Zhang, D. Ju
  • Department Of Microbiological And Biochemical Pharmacy, School of Pharmacy, Fudan University, 201203 - Shanghai/CN

Abstract

Background

CD47-targeted immune checkpoint inhibitors have shown potent anti-tumor efficacy in several malignant tumors. However, glioblastoma, one of the most malignant brain tumors in the central nervous system (CNS), was still a challenge for CD47-targeted immunotherapy.

Methods

SIRPα-Fc, a CD47-targeted fusion protein, was employed to investigate the anti-tumor efficacy of blocking CD47-SIRPα axis alone or combined with autophagy depletion in glioblastoma. Confocal microscopy, transmission electron microscopy and western blot were used to detect autophagy. Glioblastoma xenograft tumors were established to investigate the synergistic anti-tumor effect of simultaneously blocking CD47-SIRPα axis and autophagy in glioblastoma. Syngeneic immunocompetent glioblastoma models were established to detect the role of adaptive immune response in SIRPα-Fc-treated glioblastoma.

Results

SIRPα-Fc has potent anti-glioblastoma efficacy via increasing macrophages phagocytosis and cytotoxicity against glioblastoma cells. Meanwhile, autophagy and autophagic flux were markedly triggered by SIRPα-Fc in glioblastoma cells through inactivation of Akt/mTOR. Importantly, abolishment of the autophagy by pharmacological inhibitors or siRNA enhanced SIRPα-Fc-induced macrophage phagocytosis and cytotoxicity against glioblastoma cells. Simultaneously blocking CD47-SIRPα axis and autophagy increased macrophages infiltration and tumor cell apoptosis, eliciting enhanced anti-glioblastoma efficacy and prolonged survival of tumor-bearing mice compared with treatment with SIRPα-Fc alone. Furthermore, adaptive immune responses, mainly including CD8+ T cells, were also involved in the anti-glioblastoma efficacy of SIRPα-Fc.

Conclusions

Our data revealed that SIRPα-Fc could elicit potent anti-glioblastoma efficacy, combined with autophagy inhibition significantly enhanced the anti-glioblastoma efficacy, which highlighted a potential therapeutic approach for glioblastoma through disrupting CD47-SIRPα axis alone or combined with autophagy depletion.

Clinical trial identification

Legal entity responsible for the study

Fudan University

Funding

None

Disclosure

All authors have declared no conflicts of interest.