Abstract 1374: Targeting CD47/SIRPɑ axis in urologic cancer triggers enhanced phagocytosis of tumor cell and induces tumor growth inhibition

Abstract

Abstract Signal regulatory protein-α (SIRPα; CD172a or SHPS-1) is a transmembrane molecule that highly expressed on myeloid population. Binding of CD47 (integrin-associated protein, IAP) to SIRPα inhibits phagocytosis in macrophages, which acts as a mechanism of maintaining homeostasis. Tumor cells however, often time upregulate CD47 to evade immune response. Using publicly available dataset, we found that human prostate cancer cells upregulate expression of both CD47 and calreticulin, a “eat me” signal when engaged with Low density lipoprotein receptor-related protein 1 (LRP1). In addition, macrophages, monocytes and dendritic cells in human prostate cancer do have relatively high level of SIRPɑ and LRP1 expression. This finding provides the rationale of targeting CD47/SIRPɑ axis in prostate cancer to shift the balance between pro-phagocytosis and anti-phagocytosis signaling. We then moved to RM1 and B6Cap, two syngeneic prostate cancer models in immunocompetent mice. Significant tumor growth inhibition was seen in both models with anti SIRPɑ blocking antibody. Furthermore, we observed in vitro that CD47 or SIRPɑ blockage led to enhanced PC3 cell line phagocytosis by human monocyte derived macrophages (HMDMs). Same finding was found using mouse bone marrow derived macrophages (BMDMs). We then utilized ovalbumin expressing MB49 bladder cancer cell line and cocultured those with BMDMs. CD8+ T cell from OT1 mice exhibited higher expression of activation makers when cocultured BMDMs treated by either anti CD47 or SIRPɑ antibody, indicating that enhanced phagocytosis subsequently increases antigen cross presentation in macrophages. In summary, we identified that CD47 is overexpressed in human prostate cancer; blocking CD47/SIRPɑ did inhibit tumor growth through enhanced phagocytosis and antigen presentation. Citation Format: Fan Shen, Monali Praharaj, Alex J. Lee, Thomas R. Nirschl, Xiaoxu Wang. Targeting CD47/SIRPɑ axis in urologic cancer triggers enhanced phagocytosis of tumor cell and induces tumor growth inhibition [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 1374.