The Immunotherapeutic Effect of SIRPα-Silenced DCs against Cervical Cancer.

Xiaojie Li,Zhizhi Xie,Jiayin Liang,Yanlan Liang,Bo Hu,Wenying Zhou,Changzhi Xu

doi:10.1155/2020/1705187

Xiaojie Li, Zhizhi Xie + Show 5 more

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https://doi.org/10.1155/2020/1705187

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Abstract

Signal regulatory protein α (SIRPα), a transmembrane protein that is predominantly expressed in dendritic cells (DCs) or macrophages, interacts with CD47 that is overexpressed in almost all types of tumor cells. The interaction between SIRPα and CD47 leads to a negative signal that prevents the phenotypic and functional maturation of DC and inhibits phagocytosis. The SIRPα knockdown in DCs that were pulsed with a modified HPV16E7 (HPV16mE7) protein with enhanced antigenicity and reduced transformation activity results in increased cytokine (TNF-α/IL-12/IL-6) secretion, IFN-γ secretion by T lymphocytes, and in vitro/in vivo tumoricidal activity against cervical cancer cells. Taken together, these results suggest that SIRPα-silenced DC vaccination presented potential therapeutic implications against cervical cancer.

Highlights

Signal regulatory protein α (SIRPα), an inhibitory transmembrane receptor expressed especially abundant in macrophages and dendritic cells (DCs), when engaged by its ligand CD47 which is a widely distributed membrane protein, transmits a “do not eat me signal” to the macrophages and delivers a negative signal to DCs, inhibiting phagocytosis of CD47-expressing cells and preventing the phenotypic and functional maturation of DCs [1,2,3,4,5]
The interaction between SIRPα on DCs with CD47 on T cells is important for regulating the priming of naive T cells, which differentiate into T helper cells, or induction of antigen-specific cytotoxic T cell responses by DCs [15]
Current focus on immunotherapy had been targeted toward inhibiting CD47-SIRPα interaction via anti-CD47 or anti-SIRPα antibodies [16]

Summary

Introduction

SIRPα, an inhibitory transmembrane receptor expressed especially abundant in macrophages and DCs, when engaged by its ligand CD47 which is a widely distributed membrane protein, transmits a “do not eat me signal” to the macrophages and delivers a negative signal to DCs, inhibiting phagocytosis of CD47-expressing cells and preventing the phenotypic and functional maturation of DCs [1,2,3,4,5]. The interaction between SIRPα and CD47 on DCs counteracts the phenotypic and functional maturation of DC by inhibiting cytokine production such as IL-12/TNF-α/IFN-γ [2, 10,11,12]. Among these cytokines, IL-12 plays a key role in inducing IFN-γ production through enhancing NK cell cytotoxicity and promoting cytotoxic T cell development [13]. IL-12 plays a key role in inducing IFN-γ production through enhancing NK cell cytotoxicity and promoting cytotoxic T cell development [13] Attributed to their capacity to produce IL-12, DCs are critically positioned to initiate the Th1 immune response [14]. Current focus on immunotherapy had been targeted toward inhibiting CD47-SIRPα interaction via anti-CD47 or anti-SIRPα antibodies [16]

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