TNFR1 Suppression by XPro1595 Reduces Peripheral Neuropathies Associated with Perineural Invasion in Female Mice

Area of Science:

• Oncology
• Neuroscience
• Immunology

Background:

• Perineural invasion (PNI) is cancer spreading into nerves, causing pain and poor prognosis.
• Soluble tumor necrosis factor alpha (solTNFα) signaling via TNFR1 drives PNI-associated inflammation and nerve injury.
• Targeting solTNFα-TNFR1 is a potential strategy for managing PNI.

Purpose of the Study:

• To investigate the efficacy of blocking solTNFα-TNFR1 signaling in a mouse model of PNI.
• To evaluate the effects of TNFR1 knockout and XPro1595 pharmacological inhibition on PNI-related pain and tumor progression.

Main Methods:

• Utilized a mouse sciatic nerve PNI model.
• Administered TNFR1 knockout and XPro1595 pharmacological inhibitor.
• Assessed tumor burden, mechanical allodynia, muscle function, locomotion, and performed histological and transcriptomic analyses.

Main Results:

• XPro1595 treatment, unlike TNFR1 knockout, reduced tumor burden and alleviated pain and motor deficits, predominantly in females.
• Histology in females showed XPro1595 increased myelin and dendritic cells, reduced axonal damage, and modulated immune cell populations.
• Transcriptomics revealed XPro1595 upregulated neuroprotective and immune-regulatory pathways while downregulating inflammation and tumor progression pathways in females.

Conclusions:

• XPro1595 demonstrated antitumor, neuroprotective, and analgesic effects in female mice with PNI.
• The mechanism likely involves promoting neuronal regeneration, mitochondrial function, and modulating immune responses.
• Targeting solTNFα-TNFR1 with XPro1595 offers a promising therapeutic approach for PNI.