Myeloid-Specific Acly Deletion Alters Macrophage Phenotype In Vitro and In Vivo without Affecting Tumor Growth
Kyra E de Goede1, Sanne G S Verberk1, Jeroen Baardman2
1Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands.
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.
Insights
Targeting ATP-citrate lyase (Acly) in cancer cells is promising, but may affect tumor-associated macrophages (TAMs). This study found Acly deletion in myeloid cells did not harm TAMs or tumor growth, suggesting Acly targeting is safe for these immune cells.
Area of Science:
- Oncology
- Immunology
- Metabolic pathways
Background:
- ATP-citrate lyase (Acly) is crucial for cancer cell lipid synthesis and proliferation.
- Acly inhibitors may impact tumor-associated macrophages (TAMs), key immune cells in the tumor microenvironment (TME).
- Previous in vitro studies suggested Acly deletion alters macrophage inflammatory responses.
Purpose of the Study:
- To investigate the in vivo effects of Acly deletion on myeloid cells, specifically TAMs.
- To determine if targeting Acly in macrophages elicits anti-tumor responses while sparing cancer cell proliferation.
- To assess the impact of Acly deletion on macrophage activation and tumor immune composition.
Main Methods:
- Utilized a myeloid-specific Acly knockout mouse model.
- Employed two distinct tumor models to evaluate Acly deletion effects.
- Analyzed changes in macrophage activation (IL-4 induced) and tumor immune cell composition and TAM phenotype.
Main Results:
- Acly absence in myeloid cells decreased IL-4-induced macrophage activation.
- Acly deletion resulted in minor, tumor-type-dependent alterations in tumor immune composition and TAM phenotype.
- Tumor growth was not affected by Acly deletion in myeloid cells.
Conclusions:
- Targeting Acly in macrophages does not appear to have detrimental effects on myeloid cells.
- Acly deletion in macrophages did not impair anti-tumor immunity or promote tumor growth in the studied models.
- These findings suggest that Acly is not essential for TAM function in vivo and support its therapeutic targeting in cancer.
