肿瘤细胞治疗研究
英文原题：Unleashing T cell surveillance for the eradication of quiescent persister tumor cells resistant to neoadjuvant chemotherapy.
我们的研究揭示了CD96是PTC驱动的微环境中一个此前未被认识到的脆弱性轴，为改善CRC治疗结果提供了有前景的途径。
尽管新辅助化疗（NAC）在减轻结直肠癌（CRC）肿瘤负荷方面已显示出疗效，但其对患者长期预后的影响仍然有限。在此，我们鉴定出静息态持久肿瘤细胞（PTCs）是治疗失败的关键决定因素。PTC丰度升高与不良长期预后相关，即使在表现出初始治疗反应的患者中也是如此。静息态PTCs具有侵袭性干细胞样特征，并在原位CRC小鼠模型中 orchestrate 一个以CD96 + CD8 + T细胞浸润为特征的免疫抑制微环境。CD96耗竭使CD8 + T细胞偏离耗竭轨迹，并通过增强线粒体功能促进记忆样表型。一致地，抗CD96治疗在临床前模型中有效清除PTCs。我们还构建了靶向上皮细胞黏附分子（EpCAM）且CD96表达缺陷的人嵌合抗原受体（CAR）-T细胞，其可强效靶向PTCs，并展现出显著的抗CRC治疗潜力。总体而言，我们的研究揭示了CD96是PTC驱动微环境中一个此前未被认识的可利用脆弱性轴，为改善CRC治疗结局提供了有前景的途径。
Although neoadjuvant chemotherapy (NAC) has shown efficacy in reducing tumor burden in colorectal cancer (CRC), its impact on long-term patient outcomes remains limited. Here, we identify quiescent persister tumor cells (PTCs) as a critical determinant of therapeutic failure. Elevated PTC abundance correlates with poor long-term prognosis, even in patients exhibiting an initial response to treatment. Quiescent PTCs possess aggressive stem-like traits and orchestrate an immunosuppressive microenvironment characterized by CD96 + CD8 + T cell infiltration in an orthotopic CRC mouse model. CD96 depletion diverts CD8 + T cells from an exhaustion trajectory and promotes memory-like phenotypes through enhanced mitochondrial function. Consistently, anti-CD96 therapy effectively eliminates PTCs in preclinical models. We also engineered epithelial cell adhesion molecule (EpCAM)-targeted human chimeric antigen receptor (CAR)-T cells deficient in CD96 expression, which robustly target PTCs and demonstrate remarkable therapeutic potential against CRC. Overall, our study uncovers CD96 as a previously unrecognized axis of vulnerability within the PTC-driven microenvironment, offering a promising avenue to enhance CRC therapeutic outcomes.
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