Myeloid-Specific Acly Deletion Alters Macrophage Phenotype In Vitro and In Vivo without Affecting Tumor Growth

Abstract

Cancer cells rely on ATP-citrate lyase (Acly)-derived acetyl-CoA for lipid biogenesis and proliferation, marking Acly as a promising therapeutic target. However, inhibitors may have side effects on tumor-associated macrophages (TAMs). TAMs are innate immune cells abundant in the tumor microenvironment (TME) and play central roles in tumorigenesis, progression and therapy response. Since macrophage Acly deletion was previously shown to elicit macrophages with increased pro- and decreased anti-inflammatory responses in vitro, we hypothesized that Acly targeting may elicit anti-tumor responses in macrophages, whilst inhibiting cancer cell proliferation. Here, we used a myeloid-specific knockout model to validate that absence of Acly decreases IL-4-induced macrophage activation. Using two distinct tumor models, we demonstrate that Acly deletion slightly alters tumor immune composition and TAM phenotype in a tumor type-dependent manner without affecting tumor growth. Together, our results indicate that targeting Acly in macrophages does not have detrimental effects on myeloid cells.

Illuminating histidine phosphorylation in the pancreatic tumor microenvironment

“…FACS/immunoblot analyses revealed the presence of novel forms of G-3-pHis+ ACLY protein in TAMs (Fig 4). Although the role of ACLY in myeloid cells has been explored in the literature (Covarrubias et al, 2016;de Goede et al, 2021;Lauterbach et al, 2019;Namgaladze et al, 2018;Rhee et al, 2019;Verberk et al, 2021), the expression of non-canonical ACLY isoforms in CD11b+Ly6G-myeloid cells has not been previously described and the origin and function of these isoforms is the subject of ongoing research.…”