肿瘤细胞治疗研究
英文原题：RHOA Deletion Downregulates CD19 and Promotes Dysfunctional Immune Microenvironments in CAR-T Resistant Large B-cell Lymphomas.
CD19靶向嵌合抗原受体（CAR）-T细胞是大B细胞淋巴瘤的突破性疗法，但不到一半的患者能获得持久缓解。
CD19靶向嵌合抗原受体（CAR）-T细胞是大B细胞淋巴瘤的突破性疗法，但不到一半的患者能获得持久缓解。我们此前发现RHOA缺失在进展病例中富集，然而尽管RHOA缺陷在新诊断疾病中频繁出现，其作用仍不明确。在此我们表明，RHOA缺失下调CD19，在体外和体内促进对CAR-19的细胞内在耐药。然而，CD19下降仅能部分解释耐药，且无法解释该缺失在新诊断病例中的高频率。因此，我们对免疫功能完整的RHOA缺陷淋巴瘤微环境进行了单细胞评估，发现其与CAR-19耐药患者的特征高度一致。尽管微环境中干扰素γ（IFNγ）产生增加，RHOA缺陷的肿瘤细胞本身对该细胞因子的反应受损，包括未能诱导I类MHC分子。总体而言，我们首次描述了一种在CAR-19耐药淋巴瘤中反复出现的单基因改变如何导致治疗失败。
CD19-directed chimeric antigen receptor (CAR)-T cells are breakthrough therapies for large B-cell lymphomas, but fewer than half of patients achieve durable responses. We previously showed RHOA deletions are enriched in progressing cases, but the role of RHOA deficiency is poorly defined despite frequent occurrence in newly diagnosed disease. Here we show RHOA loss downregulates CD19, promoting cell-intrinsic resistance to CAR-19 in vitro and in vivo. CD19 decline, however, provides an incomplete explanation of resistance and would not explain high frequency of the deletion in newly diagnosed cases. We therefore performed single-cell assessments of immunocompetent RHOA-deficient lymphoma microenvironments, revealing remarkable concordance with features in CAR-19-resistant patients. Despite increased microenvironmental production of interferon gamma (IFNγ), RHOA-deficient tumor cells themselves show impaired response to the cytokine including failed induction of Class I MHC molecules. Overall, we describe for the first time how a single-gene alteration recurrent in CAR-19-resistant lymphoma contributes to treatment failures.
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