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
Department of Nanoscience, Joint School of Nanoscience and Nanoengineering, University of North Carolina at Greensboro, Greensboro, NC, United States.
Department of Nanoengineering, Joint School of Nanoscience and Nanoengineering, North Carolina Agricultural and Technical (AT) State University, Greensboro, NC, United States.
Front Oncol. 2022 Apr 22;12:871390. doi: 10.3389/fonc.2022.871390. eCollection 2022.
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/-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/-positive cancer cells and 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/ tumor-specific IgE-sensitized MCs bound, penetrated, and killed HER2/-positive tumor masses . 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/ 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.
用于癌症治疗的自体细胞种类不断增加且仍在研究中。肥大细胞（MCs）是组织细胞，含有一组独特的抗癌介质，存在于肿瘤内部及其周围。我们试图利用MC颗粒中的抗肿瘤介质，通过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，并在肿瘤细胞接触时可控地触发抗肿瘤介质的释放。我们使用人HER2/特异性IgE通过高亲和力IgE受体（FcεRI）武装人MCs。评估了MCs结合并诱导HER2/阳性癌细胞凋亡的能力。使用共聚焦显微镜实时研究MCs与癌细胞之间的相互作用。使用基因阵列分析研究了细胞毒性MCs的作用机制。利用小干扰RNA（siRNA）对自体MC进行基因操作，以评估MC特异性介质对肿瘤细胞凋亡的影响。我们发现，HER2/肿瘤特异性IgE致敏的MCs能够结合、穿透并杀死HER2/阳性肿瘤块。描述了MCs与肿瘤细胞之间形成的隧道纳米管，其与肿瘤细胞凋亡平行。在实体瘤、人乳腺癌（BC）异种移植小鼠模型中，注入HER2/IgE致敏的人MCs与BC细胞共定位，减轻了肿瘤负担，延长了总生存期，且无毒性迹象。肿瘤细胞的基因微阵列表明，其依赖于肿瘤坏死因子（TNF）和转化生长因子β（TGFβ）信号通路导致细胞凋亡。敲除MC释放的类胰蛋白酶并不影响癌细胞的凋亡。这些研究表明，MCs可以从介导I型超敏反应的细胞极化成为选择性靶向肿瘤细胞并被特异性触发释放抗肿瘤介质的细胞毒性细胞。本文描述了一种研究哪些MC介质负责观察到的肿瘤杀伤作用的策略，以便未来在选择哪些介质进行靶向缺失或选择哪些介质通过添加其他已知抗肿瘤药物使其进一步极化为细胞毒性MC时能够做出合理决策。使用自体人MC可能为癌症治疗提供更多选择，其利用肿瘤靶向IgE提供了独特的抗癌作用机制。
