肿瘤细胞治疗研究
英文原题：Cell adhesion molecule ITGB2 promotes CAR-T cell therapy in B-cell malignancies.
CAR-T 细胞疗法作为肿瘤免疫治疗的代表性技术，在血液系统恶性肿瘤的治疗中已显示出显著成功；然而，仍有相当比例的患者未能获得持续缓解。
作为癌症免疫疗法的代表性技术，CAR-T细胞疗法已在血液系统恶性肿瘤治疗中取得显著成功，但相当一部分患者未能获得持久缓解。通过分析CD19 CAR-T治疗前的骨髓测序数据，我们发现细胞黏附是影响临床结局的关键因素。我们根据细胞黏附相关核心基因建立了预测B-ALL治疗效果的模型，并在临床队列中进行了验证。体外和体内实验均显示，抑制或敲除恶性B细胞中的整合素β2亚基（ITGB2，又称CD18），会显著削弱CD19和CD20 CAR-T细胞对B系肿瘤细胞的细胞毒性；ITGB2介导的细胞毒性变化与肿瘤微环境中免疫突触形成相关。值得注意的是，利用LPS或Venetoclax上调Nalm6细胞中的ITGB2，可显著增强CAR-T细胞对Nalm6细胞的杀伤活性。我们的研究结果提供了一个用于临床CD19 CAR-T疗法的新型预测模型，并阐明ITGB2通路在CAR-T细胞介导清除B细胞恶性肿瘤中的作用。
CAR-T cell therapy, as a representative technology in cancer immunotherapy, has demonstrated notable success in the treatment of hematologic malignancies; however, a significant proportion of patients fail to achieve sustained remission. Through the analysis of bone marrow sequencing data prior to CD19 CAR-T cell therapy, we identified cellular adhesion as a pivotal factor influencing clinical outcomes. We developed a model to predict B-ALL treatment efficacy based on the core genes associated with cellular adhesion, which was validated in our clinical cohort. Both in vitro and in vivo experiments revealed that the inhibition or knockout of integrin subunit beta 2 (ITGB2, also known as CD18) in malignant B cells markedly diminished the cytotoxic efficacy of both CD19 and CD20 CAR-T cells against B-lineage tumor cells, with alterations in ITGB2-mediated cytotoxicity linked to the formation of immunological synapses within the tumor microenvironment. Notably, the upregulation of ITGB2 in Nalm6 cells via LPS or Venetoclax significantly augmented the cytotoxic activity of CAR-T cells against Nalm6 cells. Our findings provide a novel predictive model for clinical CD19 CAR-T cell therapy and elucidate a role of the ITGB2 pathway in CAR-T cell-mediated eradication of B-cell malignancies.
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