Background For decades the field of oncology’s primary focus has been killing cancer. As treatment efficacy has soared so has the number of survivors, revealing an ugly truth. While cancer therapies are crucial for patient survival, they leave behind a slew of unintended and debilitating CNS damage, known as cancer-related cognitive impairments (CRCI), in their wake. Raising the question, how can we prevent CRCI? Our past radiation- and chemo-therapy studies suggest that elevated peripheral- and neuro-inflammation play a detrimental role in neural damage. While the neurobiological mechanisms and mitigation strategies for chemotherapy and radiation-induced brain injury have been determined, a comprehensive understanding of the mechanism of immune checkpoint inhibition (ICI)-induced brain injury and cognitive dysfunction remains relatively incomplete. ICI allows a T cell-mediated immune response to eliminate cancer. We hypothesize that, T cells and other infiltrating immune cells promote a systemic immune response, thereby triggering neuroinflammation leading to neuronal and synaptic damage. Our study characterizes the neuro-inflammatory and neuro-degenerative sequelae following melanoma ICI treatment leading to cognitive impairments with the hope of revealing potential therapeutic targets.

Methods C57Bl6 mice underwent melanoma tumor induction and were treated with a combinatorial ICI treatment (anti-PD1 and anti-CTLA4 antibodies) for 3-weeks. One cohort of animals was sacrificed 72 hours after the last treatment. Hippocampi and plasma were extracted and used for cytokine analysis. Lymphoid and myeloid cells were isolated from whole brains and flow cytometry was used to characterize the immune response. A month post-ICI treatment, a second cohort of mice underwent behavior testing, including anxiety, learning and memory, and memory consolidation tasks. Mice were euthanized and brains were used for dual-immunofluorescence staining and 3D algorithm-based volumetric quantification of synaptic, neuronal, and glial markers.

Results ICI treatment significantly reduced melanoma progression. Flow cytometric analysis revealed a significant increase in both myeloid and lymphoid cells within the brain, including CD4 and CD8 T cells, and activated microglia. Cytokine analysis revealed notable increases in pro-inflammatory cytokines (IL-1α, TNF- α, IL-17, IL-6, and IL-12) in the plasma from melanoma-bearing mice receiving ICI treatment. This group also showed a significant decline in performance on hippocampal-dependent learning and memory, anxiety, and memory consolidation tasks. Analysis of brain 2-month post-ICI showed reduced synaptic integrity, myelin, and elevated microglial activation in the ICI-treated brains.

Conclusions Our data present a mammalian model of cancer immunotherapy-mediated cognitive impairments and support our hypothesis that long-term neuroinflammation is a major contributing factor in CRCI.