UNLABELLED

Combinatorial blockade of Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and Programmed Cell Death Protein 1 (PD-1) significantly improve the progression-free survival of individuals with metastatic cancers, including melanoma. In addition to unleashing anti-tumor immunity, combination immune checkpoint inhibition (ICI) disrupts immune-regulatory networks critical for maintaining homeostasis in various tissues, including the central nervous system (CNS). Although ICI- and cancer-related cognitive impairments (CRCI) in survivors are increasingly becoming evident, our understanding of ICI-induced immune-related adverse effects (IREA) in the CNS remains incomplete. Here, our murine melanoma model reveals that combination ICI impairs hippocampal-dependent learning and memory, as well as memory consolidation processes. Mechanistically, combination ICI disrupted synaptic integrity, and neuronal plasticity, reduced myelin, and further predisposed CNS for exaggerated experimental autoimmune encephalomyelitis. Combination ICI substantially altered both lymphoid and myeloid cells in the CNS. Neurogenesis was unaffected, however, microglial activation persisted for two-months post- ICI, concurrently with cognitive deficits, which parallels clinical observations in survivors. Overall, our results demonstrate that blockade of CTLA-4 and PD-1 alters neuro-immune homeostasis and activates microglia, promoting long-term neurodegeneration and driving cognitive impairments. Therefore, limiting microglial activation is a potential avenue to mitigate CNS IRAE while maintaining the therapeutic benefits of rapidly evolving ICIs and their combinations.

SIGNIFICANCE

Despite the superior therapeutic efficacy of immune checkpoint inhibition (ICI) for cancers, its undesired effects on brain function are not fully understood. Here, we demonstrate that combination ICI elevates neuroinflammation, activates microglia, leading to detrimental neurodegenerative and neurocognitive sequelae.