RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
Siglec-7 糖免疫结合 mAb 或 NK 细胞衔接器生物制剂可诱导针对卵巢癌的有效抗肿瘤免疫
英文原题：Siglec-7 glyco-immune binding mAbs or NK cell engager biologics induce potent antitumor immunity against ovarian cancers.
查看英文原题
Siglec-7 glyco-immune binding mAbs or NK cell engager biologics induce potent antitumor immunity against ovarian cancers.
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中文摘要
卵巢癌（OC）是一种致命的妇科恶性肿瘤，对CPI的应答有限。调动额外的免疫臂，如NK细胞，可能具有价值。我们聚焦于Siglec-7作为调动该细胞群的表面抗原。开发并表征了针对Siglec-7的人源抗体。OC细胞与PBMCs/NKs及Siglec-7结合抗体共培养显示NK介导的对OC细胞系的杀伤。抗Siglec-7 mAb（DB7.2）提高了OC攻击小鼠的生存率。此外，DB7.2与抗PD-1联合在体外显示出进一步改善的OC杀伤。为将Siglec-7调动作为OC特异性策略，我们工程化了一种NK细胞衔接器（NKCE），通过Siglec-7同时衔接NK细胞，并通过FSHR衔接OC靶点。该NKCE在体外显示出对FSHR+ OC的强效杀伤，控制了肿瘤，并提高了OC攻击小鼠的生存率。这些研究支持进一步探索Siglec-7靶向方法作为OC及其他难治性癌症的重要工具。
展开英文摘要原文
Ovarian cancer (OC) is a lethal gynecologic malignancy, with modest responses to CPI. Engagement of additional immune arms, such as NK cells, may be of value.
We focused on Siglec-7 as a surface antigen for engaging this population. Human antibodies against Siglec-7 were developed and characterized. Coculture of OC cells with PBMCs/NKs and Siglec-7 binding antibodies showed NK-mediated killing of OC lines. Anti-Siglec-7 mAb (DB7. 2) enhanced survival in OC-challenged mice.
In addition, the combination of DB7. 2 and anti-PD-1 demonstrated further improved OC killing in vitro. To use Siglec-7 engagement as an OC-specific strategy, we engineered an NK cell engager (NKCE) to simultaneously engage NK cells through Siglec-7, and OC targets through FSHR. The NKCE demonstrated robust in vitro killing of FSHR + OC, controlled tumors, and improved survival in OC-challenged mice. These studies support additional investigation of the Siglec-7 targeting approaches as important tools for OC and other recalcitrant cancers.
论文信息
- 作者
- Bordoloi D、Kulkarni AJ、Adeniji OS、Pampena MB、Bhojnagarwala PS、Zhao S、Ionescu C、Perales-Puchalt A
- 单位
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, USA.United States
- 期刊
- Science advances2023 Nov 3
- 原文标识
- PubMed 37910620 · DOI 10.1126/sciadv.adh4379
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