美国斯坦福大学Michelle Monje课题组取得一项新突破。他们开发出CAR-T细胞治疗后小鼠免疫治疗相关的认知障碍。2025年5月12日出版的《细胞》杂志发表了这项成果。

课题组研究人员在小鼠模型中证明，嵌合抗原受体（CAR）T细胞治疗中枢神经系统（CNS）和非中枢神经系统癌症会损害认知功能，并诱导持续的中枢神经系统免疫反应，其特征是白质小胶质反应性、小胶质趋化因子表达以及脑脊液（CSF）细胞因子和趋化因子升高。因此，少突胶质内平衡和海马神经发生被破坏。接受或未接受CAR-T细胞治疗的脑干肿瘤患者的人类额叶单核测序研究，证实了治疗后小胶质细胞和少突胶质细胞的反应状态。

在一项CAR-T细胞治疗后的小鼠注意力和短期记忆功能行为测试中，短暂性小胶质细胞耗散或CCR3趋化因子受体阻断可挽救少突胶质细胞缺陷和认知表现。综上所述，这些发现阐明了免疫治疗相关认知障碍的可靶向神经免疫机制。

据悉，免疫疗法已经彻底改变了许多肿瘤类型的癌症治疗，但其潜在的长期认知影响尚不完全清楚。

附：英文原文

Title: Immunotherapy-related cognitive impairment after CAR T cell therapy in mice

Author: Anna C. Geraghty, Lehi Acosta-Alvarez, Maria C. Rotiroti, Selena Dutton, Michael R. O’Dea, Wonju Kim, Vrunda Trivedi, Rebecca Mancusi, Kiarash Shamardani, Karen Malacon, Pamelyn J. Woo, Naiara Martinez-Velez, Theresa Pham, Noemi N. Reche-Ley, Gabriel Otubu, Enrique H. Castenada, Kamsi Nwangwu, Haojun Xu, Sara B. Mulinyawe, Daniel B. Zamler, Lijun Ni, Kevin Cross, Justin Rustenhoven, Jonathan Kipnis, Shane A. Liddelow, Crystal L. Mackall, Robbie G. Majzner, Michelle Monje

Issue&Volume: 2025-05-12

Abstract: Immunotherapies have revolutionized cancer care for many tumor types, but their potential long-term cognitive impacts are incompletely understood. Here, we demonstrated in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impaired cognitive function and induced a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis were disrupted. Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes following treatment. In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescued oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T cell therapy. Taken together, these findings illustrate targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.

DOI: 10.1016/j.cell.2025.03.041

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00391-5