免疫突触形成作为T细胞依赖性双特异性抗体介导的免疫激活和细胞毒性的关键机制。
Immunological synapse formation as a key mechanism in T cell-dependent bispecific antibody-mediated immune activation and cytotoxicity.
作者信息
Nakamura Rikuto, Tsumura Ryo, Anzai Takahiro, Asano Ryutaro, Yasunaga Masahiro
机构信息
Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, 277-8577, Japan.
Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, 277-8562, Japan.
出版信息
Cancer Immunol Immunother. 2025 Jun 21;74(8):246. doi: 10.1007/s00262-025-04036-w.
T cell-dependent bispecific antibodies (TDBs) are next-generation antibody therapies that link cancer cells and T cells to achieve potent antitumor effects. Despite the successful development of TDBs for hematological malignancies, their efficacy against solid tumors remains limited. Overcoming this challenge requires a deeper understanding of their mechanisms of action. While the basic process of immunological synapse (IS) formation and T cell activation by TDB is known, the detailed effects of IS on the bystander effect and T cell migration, both crucial for therapeutic efficacy, remain unclear. This study investigated these mechanisms using an EGFR/CD3 TDB (hEx3) and EGFR knockout cancer cells (KO). The results revealed that IS formation by TDB induced a bystander effect, leading to damage in surrounding KO, with the extent depending on the proportion of EGFR-positive wild-type cancer cells (WT) and the duration of co-culture. Furthermore, IS formation significantly enhanced T cell cytokine and chemokine secretion, promoting T cell migration. These findings provide critical insights into TDB efficacy mechanisms and highlight the importance of evaluating IS formation in developing new antibody drugs. Establishing a reliable system for assessing IS formation will be essential for advancing TDBs and other antibody-based therapies, particularly against solid tumors.
T细胞依赖性双特异性抗体(TDBs)是新一代抗体疗法,可将癌细胞与T细胞连接起来,以实现强大的抗肿瘤效果。尽管TDBs在血液系统恶性肿瘤的治疗中取得了成功,但它们对实体瘤的疗效仍然有限。克服这一挑战需要更深入地了解其作用机制。虽然TDB诱导免疫突触(IS)形成和T细胞活化的基本过程是已知的,但IS对旁观者效应和T细胞迁移的详细影响(这两者对治疗效果都至关重要)仍不清楚。本研究使用EGFR/CD3 TDB(hEx3)和EGFR基因敲除癌细胞(KO)对这些机制进行了研究。结果显示,TDB诱导的IS形成会引发旁观者效应,导致周围KO细胞受损,其程度取决于EGFR阳性野生型癌细胞(WT)的比例和共培养时间。此外,IS形成显著增强了T细胞细胞因子和趋化因子的分泌,促进了T细胞迁移。这些发现为TDB的疗效机制提供了关键见解,并突出了在开发新抗体药物时评估IS形成的重要性。建立一个可靠的评估IS形成的系统对于推进TDB和其他基于抗体的疗法,尤其是针对实体瘤的疗法至关重要。
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