Immune checkpoint inhibition perturbs neuro-immune homeostasis and impairs cognitive function

Blockade of Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed Cell Death Protein 1 (PD-1) significantly improves progression-free survival in patients with cancers, including melanoma. In addition to unleashing antitumor immunity, immune checkpoint inhibition (ICI) therapies disrupt immune regulatory networks critical for maintaining homeostasis in various tissues, including the central nervous system (CNS). Despite growing reports of cancer- and ICI-related cognitive impairments among survivors, our understanding of the pathophysiology of ICI-related neurodegenerative effects is limited.

In this study, we used a murine model of melanoma, cognitive function tests, and neuroimmunological assays to investigate the cellular mechanisms and impact of combinatorial blockade of CTLA-4 and PD-1 on brain function. Syngeneic melanoma was induced in C57Bl6 mice via intradermal injection of D4M-3A.UV2 melanoma cells. After confirmation of tumor growth, cancer-bearing and non-cancer mice received combinatorial treatment of anti-CTLA-4 (1 mg per dose, twice per week) and anti-PD-1 (200 µg per dose, thrice per week) for three weeks. One month after completing ICI treatment, mice were evaluated for learning, memory, and memory consolidation cognitive function tasks. Neuroinflammation, synaptic and myelin integrity, and immune cell status in the brain were analyzed to examine neuro-immunological changes post-ICI treatment.

While tumor-related alterations in brain function were evident, combined ICI treatment specifically disrupted synaptic integrity and reduced myelin levels independent of neurogenesis and neuronal plasticity in both cancer-bearing and non-cancer mice brains. Combined ICI selectively impaired hippocampal-dependent cognitive function. This was associated with a two-fold increase in T cell numbers within the brain along with immune activation of myeloid cells, especially microglia. Furthermore, an experimental autoimmune encephalomyelitis model revealed that combination ICI predisposes the CNS to exacerbated autoimmunity, highlighting neuroinflammation-related, and tumor-independent, neurodegenerative sequelae of combination ICI.

Our results demonstrate that combinatorial blockade of CTLA-4 and PD-1 destabilizes neuroimmune-regulatory networks and activates microglia, contributing to long-term neurodegeneration and cognitive impairments. Therefore, selectively limiting microglial activation could be a potential avenue to preserve CNS functions while maintaining the therapeutic benefits of rapidly evolving ICIs and their combinations.