Immune Checkpoint Inhibition-related Neuroinflammation Disrupts Cognitive Function.

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.

Complement C5a receptor 1 blockade reverses cognitive deficits following cranial radiation therapy for brain cancer.

Cranial radiation therapy (RT) for brain cancers leads to an irreversible decline in cognitive function without an available remedy. Radiation-induced cognitive deficits (RICD) are particularly a pressing problem for the survivors of pediatric and low grade glioma (LGG) patients who often live long post-RT. Radiation-induced elevated neuroinflammation and gliosis, triggered by the detrimental CNS complement cascade, lead to excessive synaptic and cognitive loss. Using intact and brain cancer-bearing mouse models, we now show that targeting anaphylatoxin complement C5a receptor (C5aR1) is neuroprotective against RICD. We used a genetic knockout, C5aR1 KO mouse, and a pharmacologic approach, employing the orally active, brain penetrant C5aR1 antagonist PMX205, to reverse RICD. Irradiated C5aR1 KO and WT mice receiving PMX205 showed significant neurocognitive improvements in object recognition memory and memory consolidation tasks. C5aR1 inhibition reduced microglial activation, astrogliosis, and synaptic loss in the irradiated brain. Importantly, C5aR1 inhibition in the syngeneic, orthotopic astrocytoma, and glioblastoma-bearing mice protected against RICD without interfering with the therapeutic efficacy of RT to reduce tumor volume in vivo . PMX205 is currently in clinical trials for amyotrophic lateral sclerosis (ALS). Thus, C5aR1 inhibition is a translationally feasible approach to address RICD, an unmet medical need.

BDNF Augmentation Using Riluzole Reverses Doxorubicin-Induced Decline in Cognitive Function and Neurogenesis.

Cancer-related cognitive impairment (CRCI) considerably affects the quality of life of millions of cancer survivors. Brain-derived neurotrophic factor (BDNF) has been shown to promote survival, differentiation, and maintenance of in vivo dentate neurogenesis, and chemotherapy induces a plethora of physiological and cellular alterations, including a decline in neurogenesis and increased neuroinflammation linked with cognitive impairments. In our clinical studies, breast cancer patients treated with doxorubicin (Adriamycin®, ADR) experienced a significant reduction in the blood levels of BDNF that was associated with a higher risk of CRCI. Our past rodent studies in CRCI have also shown a significant reduction in dentate neurogenesis accompanied by cognitive impairment. In this study, using a female mouse model of ADR-induced cognitive decline, we tested the impact of riluzole (RZ), an orally active BDNF-enhancing medication that is FDA-approved for amyotrophic lateral sclerosis. ADR-treated mice receiving RZ in the drinking water for 1 month showed significant improvements in hippocampal-dependent learning and memory function (spatial recognition), fear extinction memory consolidation, and reduced anxiety-like behavior. RZ prevented chemotherapy-induced reductions of BDNF levels in the hippocampus. Importantly, RZ mitigated chemotherapy-induced loss of newly born, immature neurons, dentate neurogenesis, and neuroinflammation. In conclusion, this data provides pre-clinical evidence for a translationally feasible approach to enhance the neuroprotective effects of RZ treatment to prevent CRCI.