Liu Xiaohong, Sun Yue, Lin Boxu, Xiong Hao, Lu Xinyue, Tan Binghe, Zhang Chenglin, Liu Mingyao, Qin Juliang, Zhang Na, Du Bing
Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
BRL Medicine Inc., Shanghai, 201109, China.
Genome Med. 2025 Jun 2;17(1):64. doi: 10.1186/s13073-025-01490-0.
Chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable success in treating hematologic malignancies. However, its efficacy against solid tumors remains limited. One of the major challenges is the lack of specific tumor antigens. Therefore, the exploration and rational selection of novel tumor targets is urgently needed. In this study, we investigate the therapeutic potential of targeting CD155 in cancer by CAR-T cells.
The expression of CD155 was analyzed across various cancer types using data from The Cancer Genome Atlas (TCGA) and validated by tissue microarray analysis. The impact of CD155 on T cell mediated cytotoxicity was analyzed using CD155 over-expression or knockout tumor cells. Subsequently, second-generation CAR-T cells were constructed using either the extracellular domain (ECD) of TIGIT or an anti-CD155 scFv to evaluate their anti-tumor efficacy both in vitro and in vivo.
We demonstrated that CD155 is specifically overexpressed across various cancer types and that its high expression is strongly associated with poor prognosis, as revealed by data from TCGA. Consistently, CD155 is significantly upregulated in clinical tumor tissues and in numerous cancer cell lines, while it is rarely expressed in normal tissues. Furthermore, CD155 expression is also significantly increased in granulocytes derived from cancer patients compared to those from healthy donors. Functionally, high CD155 expression significantly inhibits the release of cytotoxic factors from T cells, thereby functioning as an immune checkpoint that mediates tumor immune evasion. After comparison, the scFv based anti-CD155 CAR-T cells demonstrated stronger anti-tumor activity than ECD of TIGIT based CAR-T cells. Moreover, the scFv based CAR-T cells exhibited effective anti-tumor activity against multiple CD155 solid and hematologic tumors both in vitro and in different xenograft mouse models.
Our study demonstrates that CD155 is selectively expressed in cancer cells while being rarely detected in normal tissues, and may serve as a promising pan-cancer target for CAR-T therapy. Targeting CD155 with CAR-T cells provides an effective approach to treating both solid and hematologic malignancies.
嵌合抗原受体T（CAR-T）细胞疗法在治疗血液系统恶性肿瘤方面已显示出显著成效。然而，其对实体瘤的疗效仍然有限。主要挑战之一是缺乏特异性肿瘤抗原。因此，迫切需要探索和合理选择新型肿瘤靶点。在本研究中，我们调查了CAR-T细胞靶向癌症中CD155的治疗潜力。
使用来自癌症基因组图谱（TCGA）的数据分析了CD155在各种癌症类型中的表达，并通过组织微阵列分析进行了验证。使用CD155过表达或敲除肿瘤细胞分析了CD155对T细胞介导的细胞毒性的影响。随后，使用TIGIT的细胞外结构域（ECD）或抗CD155单链抗体片段（scFv）构建第二代CAR-T细胞，以评估它们在体外和体内的抗肿瘤疗效。
我们证明，如TCGA数据所示，CD155在各种癌症类型中特异性过表达，其高表达与不良预后密切相关。一致的是，CD155在临床肿瘤组织和众多癌细胞系中显著上调，而在正常组织中很少表达。此外，与健康供体来源的粒细胞相比，癌症患者来源的粒细胞中CD155表达也显著增加。在功能上，高CD155表达显著抑制T细胞释放细胞毒性因子，从而作为介导肿瘤免疫逃逸的免疫检查点发挥作用。经过比较，基于scFv的抗CD155 CAR-T细胞表现出比基于TIGIT的ECD的CAR-T细胞更强的抗肿瘤活性。此外，基于scFv的CAR-T细胞在体外和不同的异种移植小鼠模型中均对多种CD155实体瘤和血液系统肿瘤表现出有效的抗肿瘤活性。
我们的研究表明，CD155在癌细胞中选择性表达，而在正常组织中很少检测到，并且可能作为CAR-T治疗有前景的泛癌靶点。用CAR-T细胞靶向CD155为治疗实体瘤和血液系统恶性肿瘤提供了一种有效方法。
