Eradication of Heterogeneous Tumors by T Cells Targeted with Combination Bispecific Chemically Self-assembled Nanorings.
Eradication of Heterogeneous Tumors by T Cells Targeted with Combination Bispecific Chemically Self-assembled Nanorings.
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DOI：
10.1158/1535-7163.mct-22-0515
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发表时间：
2023-03-02
影响因子：
5.7
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中科院分区：
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癌症干细胞样细胞（CSC）通常是屈光复发的根本原因，因为它们对大多数疗法具有固有的抵抗力和快速自我繁殖的能力。最近，抗原CD 133已被确定为几种癌症类型的CSC标志物，α CD 133疗法已证明可选择性靶向CSC，脱靶毒性最小。从理论上讲，通过选择性消除CSC，应该增强对大量肿瘤靶向治疗的敏感性。此前，我们的实验室已经开发出双特异性化学自组装纳米环（CSAN），成功诱导T细胞根除EpCAM阳性肿瘤。我们推断，使用我们的CSAN平台同时靶向CSC（CD 133+）和大块肿瘤（EpCAM+）应该产生协同效应。我们评估了α CD 133/α CD 3 CSAN作为单药以及与αEpCAM/α CD 3 CSAN联合治疗表达CD 133+癌症干细胞和EpCAM+大块肿瘤细胞亚群的三阴性乳腺癌（TNBC）细胞的效果。此外，原位乳腺癌模型验证了α CD 133和αEpCAM靶向联合收割机协同消除TNBC MDA-MB-231细胞的能力。只有当EpCAM和CD 133同时靶向时，肿瘤才能完全根除，并导致80%的试验小鼠完全缓解。重要的是，CD 133 TNBC的消耗和富集突出了CD 133阳性癌细胞在调节肿瘤生长和进展中的作用。总的来说，我们的结果表明，双特异性CSAN的双重靶向可以有效对抗异质性肿瘤细胞群体，并且消除原发性和CD 133 + CSC对于根除至少一个TNBC子集可能是必要的。
Cancer Stem-like Cells (CSCs) are often the root cause of refractive relapse due to their inherent resistance to most therapies and ability to rapidly self-propagate. Recently the antigen CD133 has been identified as a CSC marker on several cancer types and αCD133 therapies have demonstrated selective targeting against CSCs with minimal off-target toxicity. Theoretically, by selectively eliminating CSCs the sensitivity to bulk tumor targeting therapies should be enhanced. Previously, our laboratory has developed bispecific chemically self-assembled nanorings (CSANs) that successfully induced T-cell eradication of EpCAM positive tumors. We reasoned that targeting both CSCs (CD133+) and the bulk tumor (EpCAM+) simultaneously using our CSAN platform should produce a synergistic effect. We evaluated αCD133/αCD3 CSANs as both a single agent and in combination with αEpCAM/αCD3 CSANs to treat triple negative breast cancer (TNBC) cells which express a subpopulation of CD133+ cancer stem cells and EpCAM+ bulk tumor cells. Furthermore, an orthotopic breast cancer model validated the ability of αCD133 and αEpCAM targeting to combine synergistically in elimination of TNBC MDA-MB-231cells. Complete tumor eradication only occurred when EpCAM and CD133 were targeted simultaneously and lead to full remission in 80% of the test mice. Importantly, the depletion and enrichment of CD133 TNBCs highlighted the role of CD133 positive cancer cells in regulating tumor growth and progression. Collectively, our results demonstrate that dual targeting with bispecific CSANs can be effective against heterogenous tumor cell populations and that elimination of primary and CD133+ CSCs maybe necessary for eradication of at least a sub-set of TNBC.