Human Tumor Targeted Cytotoxic Mast Cells for Cancer Immunotherapy.
Human Tumor Targeted Cytotoxic Mast Cells for Cancer Immunotherapy.
复制标题
人肿瘤针对细胞毒性肥大细胞进行癌症免疫疗法。
DOI：
10.3389/fonc.2022.871390
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发表时间：
2022
影响因子：
4.7
通讯作者：
Kepley, Christopher L.
中科院分区：
文献类型：
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作者：
Fereydouni, Mohammad;Ahani, Elnaz;Desai, Parth;Motaghed, Mona;Dellinger, Anthony;Metcalfe, Dean D.;Yin, Yuzhi;Lee, Sung Hyun;Kafri, Tal;Bhatt, Aadra P.;Dellinger, Kristen;Kepley, Christopher L.
关键词：
用于癌症治疗和研究的自体细胞的多样性继续增加。肥大细胞（MC）是一种组织细胞，含有一组独特的抗癌介质，并在肿瘤中和周围发现。我们试图利用MC颗粒中的抗肿瘤介质，使用肿瘤特异性免疫球蛋白E（IgE）将它们选择性地靶向肿瘤细胞，并在肿瘤细胞接合时可控地触发抗肿瘤介质的释放。我们使用人HER 2/neu特异性IgE通过高亲和力IgE受体（FcεRI）来武装人MC。评估MC在体外和体内结合并诱导HER 2/neu阳性癌细胞凋亡的能力。利用共聚焦显微镜对MCs与癌细胞之间的相互作用进行了真实的研究。使用基因阵列分析检查使用细胞毒性MC的作用机制。使用siRNA开发了遗传操作自体MC以评估MC特异性介质对肿瘤细胞凋亡的影响。我们发现，HER 2/neu肿瘤特异性IgE致敏的MCs结合，穿透，并在体外杀死HER 2/neu阳性肿瘤肿块。描述了MC和肿瘤细胞之间形成的平行于肿瘤细胞凋亡的纳米管。在实体瘤、人乳腺癌（BC）异种移植小鼠模型中，输注HER 2/neu IgE致敏的人MC共定位于BC细胞，降低肿瘤负荷，延长总生存期，无毒性指征。肿瘤细胞的基因芯片提示肿瘤细胞凋亡依赖于TNF和TGFβ信号通路。敲除MC释放的类胰蛋白酶不影响癌细胞的凋亡。这些研究表明MC可以从I型超敏介导细胞极化为选择性靶向肿瘤细胞并特异性触发释放抗肿瘤介质的细胞毒性细胞。一种策略，以调查MC介质负责观察到的肿瘤杀伤，以便合理的决定，可以在未来选择哪些介质删除或那些可以进一步将它们添加到细胞毒性MC时，通过添加其他已知的抗肿瘤药物。使用自体人MC可以为癌症治疗提供进一步的选择，所述癌症治疗提供使用肿瘤靶向IgE的独特抗癌作用机制。
The diversity of autologous cells being used and investigated for cancer therapy continues to increase. Mast cells (MCs) are tissue cells that contain a unique set of anti-cancer mediators and are found in and around tumors. We sought to exploit the anti-tumor mediators in MC granules to selectively target them to tumor cells using tumor specific immunoglobin E (IgE) and controllably trigger release of anti-tumor mediators upon tumor cell engagement. We used a human HER2/neu-specific IgE to arm human MCs through the high affinity IgE receptor (FcεRI). The ability of MCs to bind to and induce apoptosis of HER2/neu-positive cancer cells in vitro and in vivo was assessed. The interactions between MCs and cancer cells were investigated in real time using confocal microscopy. The mechanism of action using cytotoxic MCs was examined using gene array profiling. Genetically manipulating autologous MC to assess the effects of MC-specific mediators have on apoptosis of tumor cells was developed using siRNA. We found that HER2/neu tumor-specific IgE-sensitized MCs bound, penetrated, and killed HER2/neu-positive tumor masses in vitro. Tunneling nanotubes formed between MCs and tumor cells are described that parallel tumor cell apoptosis. In solid tumor, human breast cancer (BC) xenograft mouse models, infusion of HER2/neu IgE-sensitized human MCs co-localized to BC cells, decreased tumor burden, and prolonged overall survival without indications of toxicity. Gene microarray of tumor cells suggests a dependence on TNF and TGFβ signaling pathways leading to apoptosis. Knocking down MC-released tryptase did not affect apoptosis of cancer cells. These studies suggest MCs can be polarized from Type I hypersensitivity-mediating cells to cytotoxic cells that selectively target tumor cells and specifically triggered to release anti-tumor mediators. A strategy to investigate which MC mediators are responsible for the observed tumor killing is described so that rational decisions can be made in the future when selecting which mediators to target for deletion or those that could further polarize them to cytotoxic MC by adding other known anti-tumor agents. Using autologous human MC may provide further options for cancer therapeutics that offers a unique anti-cancer mechanism of action using tumor targeted IgE’s.
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影响因子：
--
作者：
Ammendola M;Leporini C;Marech I;Gadaleta CD;Scognamillo G;Sacco R;Sammarco G;De Sarro G;Russo E;Ranieri G
通讯作者：
Ranieri G
影响因子：
7.4
作者：
Josephs SF;Ichim TE;Prince SM;Kesari S;Marincola FM;Escobedo AR;Jafri A
通讯作者：
Jafri A
影响因子：
15.9
作者：
Blair, RJ;Meng, H;Gruber, BL
通讯作者：
Gruber, BL
影响因子：
5.2
作者：
Choi, Jung-A;Kwon, Hyunja;Kim, Jae-Hoon
通讯作者：
Kim, Jae-Hoon
影响因子：
64.8
作者：
GORDON, JR;GALLI, SJ
通讯作者：
GALLI, SJ