Geraghty Anna C, Acosta-Alvarez Lehi, Rotiroti Maria, Dutton Selena, O'Dea Michael R, Woo Pamelyn J, Xu Haojun, Shamardani Kiarash, Mancusi Rebecca, Ni Lijun, Mulinyawe Sara B, Kim Won Ju, Liddelow Shane A, Majzner Robbie G, Monje Michelle
Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA USA 94305.
Department of Pediatrics, Stanford School of Medicine, Stanford, CA USA 94305.
bioRxiv. 2024 May 14:2024.05.14.594163. doi: 10.1101/2024.05.14.594163.
Persistent central nervous system (CNS) immune dysregulation and consequent dysfunction of multiple neural cell types is central to the neurobiological underpinnings of a cognitive impairment syndrome that can occur following traditional cancer therapies or certain infections. Immunotherapies have revolutionized cancer care for many tumor types, but the potential long-term cognitive sequelae are incompletely understood. Here, we demonstrate in mouse models that chimeric antigen receptor (CAR) T cell therapy for both CNS and non-CNS cancers can impair cognitive function and induce a persistent CNS immune response characterized by white matter microglial reactivity and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis are disrupted. Microglial depletion rescues oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function. Taken together, these findings illustrate similar mechanisms underlying immunotherapy-related cognitive impairment (IRCI) and cognitive impairment following traditional cancer therapies and other immune challenges.
持续性中枢神经系统（CNS）免疫失调以及随之而来的多种神经细胞类型功能障碍，是传统癌症治疗或某些感染后可能出现的认知障碍综合征神经生物学基础的核心。免疫疗法已经彻底改变了许多肿瘤类型的癌症治疗方式，但潜在的长期认知后遗症尚未完全了解。在此，我们在小鼠模型中证明，针对中枢神经系统和非中枢神经系统癌症的嵌合抗原受体（CAR）T细胞疗法会损害认知功能，并引发以白质小胶质细胞反应性以及脑脊液（CSF）细胞因子和趋化因子升高为特征的持续性中枢神经系统免疫反应。因此，少突胶质细胞的稳态和海马神经发生受到破坏。在注意力和短期记忆功能的行为测试中，小胶质细胞耗竭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疗法相关认知障碍（IRCI）以及传统癌症治疗和其他免疫挑战后认知障碍背后的相似机制。
