β-blocker suppresses both tumoral sympathetic neurons and perivascular macrophages during oncolytic herpes virotherapy

• DOI: 10.1136/jitc-2024-011322
• Publication Date: 2025-04-05T13:41:27Z
• Authors: Konstantina Kyritsi; Rafal Pacholczyk; Eugene Douglass; Miao Yu; Hui Fang; Gang Zhou; Balveen Kaur; Qin Wang; David H Munn; Bangxing Hong

Background The autonomic nervous system (ANS) plays a key role in regulating tumor development and therapy resistance various solid tumors. Within the ANS, sympathetic (SNS) is typically associated with protumor effects. However, whether SNS influences antitumor efficacy of intratumoral injections oncolytic herpes simplex virus (oHSV) tumors remains unknown. Methods In this study, we examined innervation its interaction immune cell infiltration both human murine triple-negative breast cancer models during oHSV blockade on oHSV’s activity. Results Intratumor injection promotes accompanied by CD45+cell MDA-MB-468 orthotopic model 4T1 mammary model. Mechanistically, tumor-secreted factors vascular endothelial growth factor (VEGF), platelet-derived (PDGF), transforming beta (TGF-β) transcription (CREB, AP-1, MeCP2, REST), which promote innervation, were found to be upregulated oHSV-treated Combining antagonist, β-blocker, significantly increased infiltration, particularly CD8+T cells Single-cell messenger RNA sequencing revealed that specific population perivascular macrophages (pvMacs) expressing high levels VEGFA, CD206, CCL3, CCL4, suppress T-cell activation. use β-blocker reduced oHSV-induced pvMacs, transition inflammatory Hexb, enhancing diversity receptor clonotypes. Further analysis suggested TGF-β signaling within partially mediates activation Conclusion Our findings demonstrate combining enhances targeting TGF-β-mediated immunosuppression.