小W (2023-10-01 00:00):
#paper doi:https://doi.org/10.1038/s41586-023-06511-9 CD300ld on neutrophils is required for tumour-driven immune suppression 以髓系细胞含量高为特征的免疫抑制肿瘤微环境(TME)是免疫治疗的主要障碍,在肿瘤环境中,大多数髓系细胞被鉴定为具有免疫抑制的病理异常活化的中性粒细胞(PMN-MDSCs)。 跨膜蛋白 CD300ld的表达仅限于骨髓细胞,且在中性粒细胞中高表达。本文 开发了 CD300ld 敲除小鼠模型(Cd300ld-KO),验证了CD300ld通过PMN-MDSCs起作用。Cd300ld-KO小鼠肿瘤中的大多数免疫抑制细胞群减少,大多数抗肿瘤作用细胞群增加,免疫微环境从促肿瘤变为抗肿瘤。CD300ld通过下游路径 S100A8/A9 在PMN-MDSC向肿瘤的迁移和募集以及中性粒细胞向病理抑制过度中起关键作用。
IF:50.500Q1 Nature, 2023-Sep. DOI: 10.1038/s41586-023-06511-9 PMID: 37674079
CD300ld on neutrophils is required for tumour-driven immune suppression
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Abstract:
The immune-suppressive tumour microenvironment represents a major obstacle to effective immunotherapy. Pathologically activated neutrophils, also known as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), are a critical component of the tumour microenvironment and have crucial roles in tumour progression and therapy resistance. Identification of the key molecules on PMN-MDSCs is required to selectively target these cells for tumour treatment. Here, we performed an in vivo CRISPR-Cas9 screen in a tumour mouse model and identified CD300ld as a top candidate of tumour-favouring receptors. CD300ld is specifically expressed in normal neutrophils and is upregulated in PMN-MDSCs upon tumour-bearing. CD300ld knockout inhibits the development of multiple tumour types in a PMN-MDSC-dependent manner. CD300ld is required for the recruitment of PMN-MDSCs into tumours and their function to suppress T cell activation. CD300ld acts via the STAT3-S100A8/A9 axis, and knockout of Cd300ld reverses the tumour immune-suppressive microenvironment. CD300ld is upregulated in human cancers and shows an unfavourable correlation with patient survival. Blocking CD300ld activity inhibits tumour development and has synergistic effects with anti-PD1. Our study identifies CD300ld as a critical immune suppressor present on PMN-MDSCs, being required for tumour immune resistance and providing a potential target for cancer immunotherapy.
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