Immunotherapy-related cognitive impairment after CAR T cell therapy in mice
Anna C. Geraghty, Lehi Acosta-Alvarez, Maria Caterina Rotiroti, Selena Dutton, Michael R. O’Dea, Wonju Kim, Vrunda Trivedi, Rebecca Mancusi, Kiarash Shamardani, Karen Malacon, Pamelyn J. Woo, Naiara Martínez-Vélez, Theresa Pham, Noemi Reche-Ley, Gabriel Otubu, Enrique H Castenada, Kamsi Nwangwu, Haojun Xu, Sara B. Mulinyawe, Daniel Zamler, Lijun Ni, Kevin P. Cross, Justin Rustenhoven, Jonathan Kipnis, Shane A. Liddelow, Crystal L. Mackall, Robbie G. Majzner, Michelle Monje
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.