Abstract 666: Targeting the CD47/SIRPα “Do not eat me” phagocytic pathway in macrophages to improve anti-CD47 immune therapy

Abstract

Abstract The cluster of differentiation 47(CD47) is a ubiquitously expressed innate immune checkpoint transmembrane protein but is often overexpressed in cancer cells. CD47 interacts with signal regulatory protein alpha (SIRPα) on macrophages leading to tyrosine phosphatase activation and preventing myosin accumulation at the phagocytic synapse. SIRPa activation triggers the “Do not eat me” signal, negatively regulating phagocytosis in macrophages. Blockade of CD47-SIRPα is a novel immunotherapeutic approach to enhance innate antitumor responses in cancer patients, and clinical data from melanoma patients also showed promising outcomes when CD47 blockade combined with other therapeutic approaches, such as anti-PD-L1. Publications from our lab have provided compelling evidence that histone deacetylase 6 (HDAC6) inhibitors with PD1 blockade delayed tumor progression, enhanced survival, and modulated macrophage phenotype both in vitro and in vivo. The present study aimed to explore the role of HDAC 6 in the CD47/SIRPα axis in phagocytosis and innate antitumor immunity. HDAC inhibition in primary mouse bone marrow-derived macrophages and human THP1 cells enhanced the pro-inflammatory M1 macrophages while downregulating the anti-inflammatory M2 phenotype. In the subsequent studies, we found that HDAC6 inhibition diminished the expression of SIRPα and enhanced the expression of other pro-phagocytic signals, such as Lrp1, CD36, and Mfge8 in macrophages. HDAC6 inhibition also downregulated the CD47 expression in mouse and human melanoma cells. Furthermore, modulation of CD47/SIRPα by HDAC6 inhibitors leads to an increase in phagocytosis in NextA-treated macrophages, further enhanced in CD47-blocking antibodies. We also demonstrated that the combination of systemic administration of the HDAC6 inhibitor Nexturastat A and intertumoral delivery of anti-CD47 reduced SM1 melanoma growth in vivo by increasing immune cell infiltration in the tumor microenvironment. Collectively our results suggest that HDAC6 inhibitors synergize with CD47 blockade to reduce tumor growth and enhance innate antitumor immunity. Citation Format: Nithya Gajendran, Maria Gracia Hernandez, Ashutosh Yende, Zubaydah Alahmad, Xintang Li, Zuleima Munoz, Manasa Suresh, David Quiceno, Karen Tan, Maho Shibata, Satish Noonepalle, Alejandro Villagra. Targeting the CD47/SIRPα “Do not eat me” phagocytic pathway in macrophages to improve anti-CD47 immune therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 666.