Didi-Zurinam Shiran, Katzman Erel, Cohen Cyrille J
Laboratory of Tumor Immunology and Immunotherapy, The Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
Front Immunol. 2025 May 13;16:1536868. doi: 10.3389/fimmu.2025.1536868. eCollection 2025.
Tumors may utilize different strategies to escape T cell immunosurveillance. Besides the overexpression of checkpoint ligands (such as PDL1) or the secretion of immunosuppressive agents, several studies have shown that cancer aberrant sialylation can, through interaction with selected receptors such as those from the Siglec family, neutralize NK and T cell function.
Herein, we wanted to take advantage of the presence of inhibitory sialic acid ligands on the tumor cell surface to enhance T cell anti-tumor activity. To this end, we devised a novel chimeric receptor consisting of the extracellular portion of Siglec-7 and the intracellular portion of 41BB, which can convert inhibitory signals into stimulatory ones when expressed in human T-cells.
This co-stimulatory chimeric switch receptor (CSR), when co-expressed with a tumor-specific TCR, facilitated higher cytokine secretion and activation profiles following co-culture with tumor cells. Additionally, T cells equipped with Siglec-7 CSR demonstrated improved anti-tumor function .
Given the broad expression pattern of Siglec-7 ligands on tumor cells, our data suggest this CSR may act as a general adjuvant to boost TCR T cell function. Overall, this work provides an approach to improve engineered T-cell-based cancer treatment.
肿瘤可能采用不同策略逃避T细胞免疫监视。除了检查点配体（如PDL1）的过表达或免疫抑制因子的分泌外，多项研究表明，癌症异常唾液酸化可通过与某些受体（如Siglec家族的受体）相互作用，中和NK细胞和T细胞功能。
在此，我们希望利用肿瘤细胞表面抑制性唾液酸配体的存在来增强T细胞的抗肿瘤活性。为此，我们设计了一种新型嵌合受体，其由Siglec-7的细胞外部分和41BB的细胞内部分组成，当在人T细胞中表达时，它可以将抑制信号转化为刺激信号。
这种共刺激嵌合开关受体（CSR）与肿瘤特异性TCR共表达时，与肿瘤细胞共培养后能促进更高的细胞因子分泌和激活水平。此外，配备Siglec-7 CSR的T细胞表现出改善的抗肿瘤功能。
鉴于Siglec-7配体在肿瘤细胞上广泛表达，我们的数据表明这种CSR可能作为一种通用佐剂来增强TCR T细胞功能。总体而言，这项工作提供了一种改进基于工程化T细胞的癌症治疗方法。
