Recent advances in cancer therapy have increasingly focused on harnessing the body's immune system to combat cancer cells. Histone deacetylases (HDACs) play a critical role in the epigenetic regulation of gene expression by remodeling chromatin. HDAC inhibitors are recognized for their ability to induce cancer cell cycle arrest, differentiation, apoptosis, reduce angiogenesis, and modulate the immune response. Another promising therapeutic target is the CD47-SIRPα axis, which is involved in immune evasion mechanisms. CD47, expressed on the surface of cancer cells, interacts with SIRPα on myeloid cells to deliver a "do not eat me" signal, thereby inhibiting the phagocytic activity of macrophages.
Researchers at GW have developed a novel immunotherapy approach that combines HDAC6 inhibition with the blockade of the CD47-SIRPα interaction. Pre-clinical studies showed that the HDAC6 inhibitor Nexturastat A (NextA) downregulates SIRPα expression, leading to an increased presence of anti-tumorigenic M1 macrophages with enhanced phagocytic capabilities, as well as suppression of CD47 expression in melanoma cells. Additionally, the combination therapy of the NextA inhibitor and an αCD47 blocking antibody synergistically inhibited in vivo tumor growth by promoting macrophage-mediated phagocytosis. Furthermore, this therapeutic strategy was also found to enhance the anti-tumor activity of T cells and Natural Killer (NK) cells in melanoma xenografts, indicating potential broad anti-cancer efficacy.
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Figures. (A) Synergistic Anti-tumor Effect of NextA and αCD47 on SM1 melanoma bearing mice. Co-administration of NextA inhibitor and αCD47 blocking antibody significantly reduces tumor volume compared to the effects observed with either treatment alone. (B) Immunophenotyping of Tumor Showing NK Cell Response. Co-treatment with NextA inhibitor and αCD47 blocking antibody leads to a significant increase in tumor infiltration of NK cells compared to monotherapy.
Targeting HDAC6 improves anti-CD47 immunotherapy. Maria Gracia-Hernandez, Ashutosh S Yende, Nithya Gajendran, Zubaydah Alahmadi, Xintang Li, Zuleima Munoz, Karen Tan, Satish Noonepalle, Maho Shibata, Alejandro Villagra. J Exp Clin Cancer Res. 2024 Feb 27;43(1):60