肿瘤细胞治疗研究
英文原题：Exhaustion, rather than lack of infiltration and persistence, of CAR-T cells hampers the efficacy of CAR-T therapy in an orthotopic PDAC xenograft model.
Exhaustion, rather than lack of infiltration and persistence, of CAR-T cells hampers the efficacy of CAR-T therapy in an orthotopic PDAC xenograft model.
CAR-T 细胞疗法在血液肿瘤患者的治疗中已展现出令人瞩目的成功，但由于实体瘤特有的障碍，其在实体瘤中的疗效非常有限。
CAR-T 细胞疗法在血液肿瘤患者的治疗中已展现出令人瞩目的成功，但由于实体瘤特有的障碍，其在实体瘤中的疗效非常有限。同时值得注意的是，肿瘤微环境组成因肿瘤类型而异，这又在每种实体瘤中造成了独特的障碍组合。因此，阐明各自的障碍是使CAR-T疗法在实体瘤中取得成功的关键。在本研究中，我们采用了原位人PDAC异种移植模型，对肿瘤组织中CAR-T细胞的定量、空间和功能动态进行了分析，以获取克服PDAC相关障碍的方法的见解。与既往研究显示CAR-T细胞在许多实体瘤中持久性和浸润有限相反，它们在PDAC肿瘤组织中持续存在并积聚。离体分析显示，从荷原位PDAC肿瘤小鼠中在不同时间点回收的CAR-T细胞表现出逐渐丧失肿瘤反应性。CAR-T细胞肿瘤反应性的丧失与AMP活化蛋白激酶表达增加以及Mitofusin 1/ Dynamin-related protein 1比值升高相关。
Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated impressive success in the treatment of patients with hematologic tumors yet achieved very limited efficacy for solid tumors due to hurdles unique to solid tumors. It is also noted that the tumor microenvironment composition varies between tumor type, which again imposes unique set of hurdles in each solid tumor. Therefore, elucidation of individual hurdles is key to achieving successful CAR-T therapy for solid tumors. In the present study, we employed an orthotopic human PDAC xenograft model, in which quantitative, spatial and functional dynamics of CAR-T cells in tumor tissues were analyzed to obtain insights into ways of overcoming PDAC related hurdles. Contrary to previous studies that demonstrated a limited persistency and infiltration of CAR-T cells in many solid tumors, they persist and accumulated in PDAC tumor tissues. Ex vivo analysis revealed that CAR-T cells that had been recovered at different time points from mice bearing an orthotopic PDAC tumor exhibited a gradual loss of tumor reactivity. This loss of tumor reactivity of CAR-T cells was associated with the increased expression of AMP-activated protein kinase and Mitofusin 1/ Dynamin-related protein 1 ratio.
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