(P 36) MODULATION OF THE SARCOMA MICROENVIRONMENT THROUGH β-ADRENERGIC BLOCKADE

Objective: β-adrenergic signaling has emerged as a key contributor to tumor progression across multiple cancer types, yet its immunosuppressive role in soft tissue sarcoma (STS) remains poorly defined. Propranolol, a non-selective β-blocker, has shown clinical efficacy in angiosarcoma, with an orphan drug designation by EMA. In this study, we explore the anti-tumor effects of propranolol in preclinical murine models of sarcoma.

Methods: We utilized murine models of sarcoma, melanoma, breast and colon cancer. Flow cytometri for characterizing immune cell infiltration. IHC on FFPE lung sections was performed.

Results: In the MCA205 fibrosarcoma model, propranolol significantly delayed tumor growth and prolonged survival and were associated with reduced tumor angiogenesis via VEGF pathway inhibition, decreased infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs), and enhanced CD4⁺ T cell recruitment. Intratumoral CD4⁺ T cells displayed an activated phenotype, marked by increased expression of CD137 and PD-1. The therapeutic benefit of propranolol was T cell–dependent. Combining propranolol and anti-CTLA-4 synergistically improved tumor responses and extended survival than either therapy alone.

Given the high incidence of pulmonary involvement in metastatic sarcoma, we employed a preclinical model of sarcoma lung metastasis to evaluate therapeutic efficacy. Propranolol treatment reduced lung metastasis burden. Mechanistically, propranolol reduced recruitment of inflammatory monocytes to the lung and increased infiltration of CD4+ T cells. In models of melanoma, breast cancer, and colon cancer lung metastasis, propranolol similarly reduced lung metastases by reshaping the monocyte compartment and recruiting tumor reactive CD4+ T cells.

Conclusion: These findings highlight β-adrenergic blockade as a promising immunomodulatory strategy that reprograms the tumor microenvironment, enhances CD4⁺ T cell–mediated immunity, and sensitizes sarcomas to checkpoint inhibition