ArticleResearch square2025
Immune Checkpoint Inhibition Perturbs Neuro-immune Homeostasis and Impairs Cognitive Function.
Article in Research square, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
- Updated by
Authors and funding
7 authors.
Funding
Abstract
Background: Blockade of Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed Cell Death Protein 1 (PD-1) significantly improves progression-free survival of individuals 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. Methods: In this study, using a murine model of melanoma, cognitive function tests, and neuroimmunological assays, we investigate the cellular mechanisms and impact of combinatorial blockade of CTLA-4 and PD-1 on brain function. Syngeneic melanoma was induced in a C57Bl6 mouse model using D4M-3A.UV2 melanoma cells. After confirmation of tumor growth, cancer-bearing and non-cancer mice received combinatorial treatment of anti-CTLA-4 (two doses per week) and anti-PD-1 (three doses per week) for three weeks. One month after completing ICI treatment, mice were administered learning, memory, and memory consolidation cognitive function tasks. Neuroinflammation, synaptic, and myelin integrity analyses and immune cell status in the brain were conducted to analyze neuroimmunological changes post-ICI treatment. Results: While tumor-related alterations in brain function were evident, combination ICI specifically disrupted synaptic integrity and reduced myelin levels independent of neurogenesis and neuronal plasticity in both cancer-bearing and non-cancer mice brains. Combination ICI selectively impaired hippocampal-dependent cognitive function. This is associated with 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. Conclusion: 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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.