Abstract 5520: β2 adrenergic receptor signaling promotes colorectal cancer liver metastasis

Abstract Liver is the most common site for cancer metastases, which may be attributed to the hepatic immunosuppressive microenvironment. Recent studies have highlighted the immunomodulatory and tumor-supportive roles of neurotransmitter-receptor signals in various cancers. Given that various neurotransmitter receptors are expressed in the liver, we aimed to investigate their possible involvement in the metastatic-prone liver microenvironment. Single-cell RNA sequencing analysis identified ADRB2, which encodes β2-adrenergic receptor (β2-AR), as the top-upregulated neurotransmitter receptor gene in colorectal cancer (CRC) and liver metastasis in patients with CRC liver metastasis (CRLM). Co-immunofluorescence (co-IF) staining confirmed the colocalization of β2-AR with myeloid cell marker CD11b instead of T cell marker CD3 and NK cell marker CD56 in patients with CRLM. Consistently, we observed the upregulation of CD11b/β2-AR double-positive cells in the liver tissues from mice bearing CRC or CRLM compared to naïve mice through co-IF staining. High-dimensional flow cytometry analysis further revealed that β2-AR was mainly expressed in macrophages and myeloid-derived suppressor cells (MDSCs). Treatment of CRC-tumor bearing mice with pan β-AR inhibitor propranolol and β2-AR specific inhibitor showed a potential to reduce liver metastatic incidence without suppressing primary CRC. Mechanistically, β2-AR activation may upregulate the expression of S100a8/9 to enhance the immunosuppressive activity of macrophages and MDSCs, thereby promoting CRC liver metastasis. Taken together, our findings reveal the potential of targeting β2-AR signaling for the prevention and treatment of liver metastasis. This project is supported by the Hong Kong University Grants Committee through the General Research Fund (14104820, 14107622, 24110323) and the Strategic Seed Funding for Collaborative Research Scheme (SSFCRS) from the Chinese University of Hong Kong. Conflict of interest: The authors declare no conflict of interest. Citation Format: Yixuan Zhang, Jintian Chen, Thomas Ting Hei Chan, Huanyu Wang, Jiahuan Lu, Jingqing Li, Jingying Zhou. β2 adrenergic receptor signaling promotes colorectal cancer liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5520.