Caloric restriction induces macrophage reprogramming and improved epithelial ovarian cancer survival

Abstract

Abstract Calorie restriction (CR) without malnutrition is a dietary intervention where energy intake is reduced by 15 – 40%. The benefits of CR in improving various diseases and extending lifespan has led its investigation in cancer. We have reported 30% CR to limit epithelial ovarian cancer (EOC) progression. Here, we highlight the ability of CR to induce immuno-metabolic reprogramming of tumor associated macrophages and improve EOC survival. Female C57/B6 mice were injected intraperitoneally with 8 × 10 6mouse EOC ID8 (p53 +/+, p53 −/−, or ID8 p53 −/−,BRCA1−/−) cells and fed ad libitum (RD) or subjected to 30% CR. Immune profiling was done by flow cytometry. Metabolic phenotype was determined by XF seahorse analyzer. Macrophage marker were measured by qPCR and western blot. Mice on 30% CR exhibited reduced tumor progression and increased overall survival compared to RD mice in all ID8 models as indicated by median survival; ID8 p53+/+(65 vs 95 days), ID8 p53−/−(50.5 vs 76.5 days), and ID8 p53−/−,BRCA1−/−(44 vs 53 days). Immune profiling showed increase in antitumor associated pro-inflammatory macrophages (F4/80+CD38+) and decrease in protumor anti-inflammatory (F4/80+CD206+) macrophages, increasing the pro / anti-inflammatory ratio. Pro-inflammatory macrophages showed increased intracellular iNOS. The phenotype change in CR mice was accompanied with reprogrammed energy metabolism indicated by increased glycolysis, reflective of pro-inflammatory macrophages. Decrease in anti-inflammatory macrophages resulted in robust anti-tumor T cell response. A 30% CR reprograms macrophage metabolism and promotes their pro-inflammatory anti-tumor phenotype, restores antitumor immunity resulting in reduced EOC growth and improved survival R01 B11209 to RR Henry Ford Cancer institute Post Doctorate Fellowship to HS