1396 Antibody blockade of the immunoinhibitory receptor Siglec 10 polarizes tumor associated myeloid cells and promotes anti-tumor immunity
Regular and Young Investigator Award Abstracts(2022)
摘要
Background
Myeloid cells are the most abundant immune cells within the tumor microenvironment (TME) where they play important roles regulating anti-tumor immunity. Targeting myeloid-specific inhibitory receptors to modulate the TME represents an attractive strategy to improve the therapeutic outcome of current cancer immune therapies. Siglec-10 is an inhibitory receptor expressed on tumor-associated macrophages (TAMs) and dendritic cells that regulates immune cell activation via immunoreceptor tyrosine-based inhibitory motifs. Recently, Siglec-10 was shown to induce immunosuppression and promote tumor immune escape through interaction with CD24. Similarly, CD52 and vascular adhesion protein-1 have been shown to drive immunosuppression via Siglec-10, indicating that Siglec-10 functions as an inhibitory receptor through multiple ligands. Here, we report that Siglec-10 expression is upregulated in human tumors and blockade of Siglec-10 with a monoclonal antibody (mAb) enhances proinflammatory responses and delays tumor growth in vivo by modulating myeloid cell function.Methods
Siglec-10 expression was evaluated in human tumors by flow cytometry and RNA-sequencing. Anti-human Siglec-10 mAbs were generated using hybridoma technology and recombinantly produced on mouse IgG1 backbones. Internalization and function of Siglec-10 mAbs were evaluated in vitro by flow cytometry and cytokine production using isolated human CD16+ monocytes. To assess the in vivo activity of a Siglec-10 mAb, transgenic mice expressing Siglec-10 were generated and challenged with poly I:C. Anti-tumor activity of a Siglec-10 mAb was determined using the MC38 syngeneic mouse model.Results
RNA-sequencing data revealed high expression of Siglec-10 across multiple tumors compared to normal tissues, including glioblastoma, colorectal carcinoma, and kidney renal clear cell carcinoma. Specifically, Siglec-10 was found to be highly and selectively expressed on intratumor dendritic cells and macrophages. Siglec-10 mAb treatment blocked ligand binding, induced complete receptor internalization, and significantly enhanced TLR-mediated human monocyte activation in vitro. Similarly, in vivo administration of a Siglec-10 mAb induced receptor internalization and enhanced TLR-mediated inflammation as evidenced by increased levels of cytokines, such as TNF and IL-12p40 (figure 1). To assess the potential of a Siglec-10 mAb as an anti-cancer immunotherapy, we established a colon carcinoma model in Siglec-10 transgenic mice. Siglec-10 mAb blockade polarized myeloid cells towards an inflammatory phenotype, enhanced adaptive immune cell activation and promoted anti-tumor activity.Conclusions
Siglec-10 is highly expressed on tumor-associated myeloid cells and antibody blockade promotes anti-tumor immunity through activation of TAMs and dendritic cells. Our findings highlight Siglec-10 as a promising myeloid cell target for enhancing anti-tumor immunity in solid tumors.Ethics Approval
All legal and ethical requirements have been met with regards to the humane treatment of animals described in this study.查看译文
关键词
immunoinhibitory receptor siglec,antibody blockade,myeloid cells,anti-tumor
AI 理解论文
溯源树
样例
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要