肿瘤细胞治疗研究
英文原题：Next Generation CD44v6-Specific CAR-NK Cells Effective against Triple Negative Breast Cancer.
有必要开发针对三阴性乳腺癌（TNBC）的新有效疗法。
有必要开发针对三阴性乳腺癌（TNBC）的新型和有效疗法。嵌合抗原受体（CAR）自然杀伤（NK）细胞是癌症治疗中CAR-T细胞疗法的一种有前景的替代方案。在TNBC中寻找合适靶点的研究确定了CD44v6，这是一种在淋巴瘤、白血病和实体瘤中表达的黏附分子，与肿瘤发生和转移有关。我们开发了一种靶向CD44v6的下一代CAR，其整合了IL-15超激动剂和检查点抑制剂分子。我们能够证明，CD44v6 CAR-NK细胞在3D球体模型中显示出对TNBC的有效细胞毒性。IL-15超激动剂在识别TNBC上的CD44v6后被特异性释放，并促进了细胞毒性攻击。PD1配体在TNBC中上调，并促进免疫抑制性肿瘤微环境（TME）。对PD1的竞争性抑制中和了TNBC上表达的PD1配体所介导的抑制。总体而言，CD44v6 CAR-NK细胞对TME免疫抑制具有抵抗性，为治疗BC（包括TNBC）提供了一种新的治疗选择。
There is a medical need to develop new and effective therapies against triple-negative breast cancer (TNBC). Chimeric antigen receptor (CAR) natural killer (NK) cells are a promising alternative to CAR-T cell therapy for cancer. A search for a suitable target in TNBC identified CD44v6, an adhesion molecule expressed in lymphomas, leukemias and solid tumors that is implicated in tumorigenesis and metastases. We have developed a next-generation CAR targeting CD44v6 that incorporates IL-15 superagonist and checkpoint inhibitor molecules. We could show that CD44v6 CAR-NK cells demonstrated effective cytotoxicity against TNBC in 3D spheroid models. The IL-15 superagonist was specifically released upon recognition of CD44v6 on TNBC and contributed to the cytotoxic attack. PD1 ligands are upregulated in TNBC and contribute to the immunosuppressive tumor microenvironment (TME). Competitive inhibition of PD1 neutralized inhibition by PD1 ligands expressed on TNBC. In total, CD44v6 CAR-NK cells are resistant to TME immunosuppression and offer a new therapeutic option for the treatment of BC, including TNBC.
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