在过去的十年中，免疫疗法的开发激增，以增强免疫系统消除肿瘤细胞的能力。称为 T 细胞接合器 (TCE) 的双特异性抗体在这一追求中提出了一种有吸引力的策略。 TCE 旨在将细胞毒性 T 细胞引导至肿瘤细胞，从而诱导强烈激活和随后的肿瘤细胞裂解。在这项研究中，我们研究了不同 TCE 对传统 α-β (αβ) T 细胞和非常规 γ δ (γδ) T 细胞的活性。 TCE 是使用针对肿瘤相关抗原 CEACAM5 (CEA) 的骆驼单域抗体 (VHH) 以及 T 细胞受体链或 CD3 域构建的。我们发现，当用 CD3xCEA TCE 刺激时，Vγ9Vδ2 T 细胞比 αβ T 细胞表现出更强的体外抗肿瘤活性。此外，将新鲜人外周 T 细胞的激活限制为 Vγ9Vδ2 T 细胞会限制促肿瘤因子和促炎细胞因子的产生，这些因子通常与患者的毒性相关。总而言之，我们的研究结果提供了进一步的见解，表明 γδ T 细胞特异性 TCE 有望成为改善抗肿瘤免疫疗法的特异性、有效且潜在安全的分子。© 2024 作者。 《欧洲免疫学杂志》由 Wiley‐VCH GmbH 出版。

In the last decade, there has been a surge in developing immunotherapies to enhance the immune system's ability to eliminate tumor cells. Bispecific antibodies known as T cell engagers (TCEs) present an attractive strategy in this pursuit. TCEs aim to guide cytotoxic T cells toward tumor cells, thereby inducing a strong activation and subsequent tumor cell lysis. In this study, we investigated the activity of different TCEs on both conventional alpha-beta (αβ) T cells and unconventional gamma delta (γδ) T cells. TCEs were built using camelid single-domain antibodies (VHHs) targeting the tumor-associated antigen CEACAM5 (CEA), together with T cell receptor chains or a CD3 domain. We show that Vγ9Vδ2 T cells display stronger in vitro antitumor activity than αβ T cells when stimulated with a CD3xCEA TCE. Furthermore, restricting the activation of fresh human peripheral T cells to Vγ9Vδ2 T cells limited the production of protumor factors and proinflammatory cytokines, commonly associated with toxicity in patients. Taken together, our findings provide further insights that γδ T cell-specific TCEs hold promise as specific, effective, and potentially safe molecules to improve antitumor immunotherapies.© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.