Immune Checkpoint Inhibition-related Neuroinflammation Disrupts Cognitive Function

Area of Science:

• Neuroscience
• Immunology
• Oncology

Background:

• Combination immune checkpoint inhibition (ICI) of CTLA-4 and PD-1 improves cancer survival but can disrupt CNS homeostasis.
• Cancer-related cognitive impairments (CRCI) and ICI-induced neuroinflammation are emerging clinical concerns.
• The precise mechanisms of ICI-induced neuroinflammation and cognitive deficits remain incompletely understood.

Purpose of the Study:

• To investigate the impact of combination ICI on cognitive function and neuro-immune pathways in a murine melanoma model.
• To elucidate the cellular and molecular mechanisms underlying ICI-induced central nervous system (CNS) adverse effects.
• To identify potential therapeutic targets for mitigating CNS immune-related adverse effects (IRAE).

Main Methods:

• Utilized a murine melanoma model treated with combination CTLA-4 and PD-1 blockade.
• Assessed cognitive function using hippocampal-dependent learning and memory tests.
• Analyzed CNS tissue for synaptic integrity, neuronal plasticity, myelin integrity, neurogenesis, and immune cell infiltration (lymphoid and myeloid).
• Investigated microglial activation and its persistence post-ICI.

Main Results:

• Combination ICI significantly impaired hippocampal-dependent learning and memory, including memory consolidation.
• Neuroinflammation was induced, characterized by disrupted synaptic integrity, reduced neuronal plasticity, and myelin loss.
• While neurogenesis was unaffected, microglial activation persisted for two months post-ICI, correlating with cognitive deficits.
• CNS lymphoid and myeloid cell populations were substantially altered.

Conclusions:

• Combination CTLA-4 and PD-1 blockade disrupts neuro-immune homeostasis, leading to long-term neurodegeneration and cognitive impairment.
• Sustained microglial activation is a key driver of CNS IRAE following combination ICI.
• Targeting microglial activation presents a promising strategy to mitigate CNS IRAE while preserving the anti-tumor efficacy of ICI.