Biology subjects

Hijaz, M.

Publications and source records attributed to Hijaz, M..

3 recordsLinked to original sources

bioRxiv2025

Aging-Driven Immunosuppression: The Role of Tregs in the Ovarian Tumor Microenvironment

Epithelial ovarian cancer (EOC) incidence and mortality increase with age, driven in part by chronic inflammation, diminished T cell output, and heightened regulatory T cell (Treg)-mediated immunosuppression. In aged EOC-bearing mice, we observed reduced survival, accompanied by impaired CD4 and CD8T cell responses and a marked expansion of FOXP3 Tregs exhibiting elevated IL-10 and TGF{beta} expression. Metabolic profiling revealed enhanced oxidative phosphorylation in Tregs from aged mice, along with a fivefold increase in intracellular succinate levels. This accumulation of succinate within the aged tumor microenvironment was found to potentiate Treg suppressive function. Notably, pharmacologic inhibition of -ketoglutarate dehydrogenase reversed this effect, restoring effector T cell activity. These findings highlight succinate driven metabolic reprogramming as a central mechanism of age related Treg dysfunction in EOC and suggest that targeting succinate metabolism may offer a promising strategy to rejuvenate antitumor immunity in elderly patients.

immunology↗

bioRxiv2024

Targeting mitochondrial metabolism with CPI-613 in chemoresistant ovarian tumors

BackgroundThere is evidence indicating that chemoresistance in tumor cells is mediated by the reconfiguration of the tricarboxylic acid cycle, leading to heightened mitochondrial activity and oxidative phosphorylation (OXPHOS). Previously, we have shown that ovarian cancer cells that are resistant to chemotherapy display increased OXPHOS, mitochondrial function, and metabolic flexibility. To exploit this weakness in chemoresistant ovarian cancer cells, we examined the effectiveness of the mitochondrial inhibitor CPI-613 in treating preclinical ovarian cancer. MethodsChemosensitive OVCAR3, and chemoresistant CAOV3 and F2 ovarian cancer cells lines and their xenografts in nude mice were used. Functional metabolic studies were performed using Seahorse instrument. Metabolite quantification was performed using LC/MS/MS. ResultsMice treated with CPI-613 exhibited a notable increase in overall survival and a reduction in tumor development and burden in OVCAR3, F2, and CAOV3 xenografts. CPI-613 suppressed the activity of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complex, which are two of its targets. This led to a reduction in OXPHOS and tricarboxylic acid cycle activity in all 3 xenografts. The addition of CPI-613 enhanced the responsiveness of chemotherapy in the chemoresistant F2 and CAOV3 tumors, resulting in a notable improvement in survival rates and a reduction in tumor size as compared to using chemotherapy alone. CPI-613 reduced the chemotherapy-induced OXPHOS in chemoresistant tumors. The study revealed that the mechanism by which CPI-613 inhibits tumor growth is through mitochondrial collapse. This is evidenced by an increase in superoxide production within the mitochondria, a decrease in ATP generation, and the release of cytochrome C, which triggers mitochondria-induced apoptosis. Our study demonstrates the translational potential of CPI-613 against chemoresistant ovarian tumors.

cancer biology↗

bioRxiv2023

Intermittent Fasting induced ketogenesis inhibits mouse epithelial ovarian tumors by promoting anti-tumor T cell response.

Epithelial Ovarian Cancer (EOC) is the most lethal gynecologic cancer with limited genetic alterations identified that can be therapeutically targeted. In tumor bearing mice, short-term fasting, fasting mimicking diet and calorie restriction enhance the activity of antineoplastic treatment by modulating systemic metabolism and boosting anti-tumor immunity. We tested the outcome of sixteen-hour intermittent fasting (IF) on mouse EOC progression with focus on fasting driven antitumor immune responses. IF resulted in consistent decrease of tumor promoting metabolic growth factors and cytokines, recapitulating changes that creates a tumor antagonizing environment. Immune profiling revealed that IF profoundly reshapes anti-cancer immunity by inducing increase in CD4+ and CD8+ cells, paralleled by enhanced antitumor Th1 and cytotoxic responses, by enhancing their metabolic fitness. Metabolic studies revealed that IF generated bioactive metabolite BHB which can be a potential substitute for simulating the antitumor benefits of IF. However, in a direct comparison, IF surpassed exogenous BHB therapy in improving survival and activating anti-tumor immune response. Thus, our data provides strong evidence for IF and its metabolic mediator BHB for ameliorating EOC progression and as a viable approach in maintaining and sustaining an effective anti-tumor T cell response.

cancer biology↗