“Treatment of cancer patients with lipid metabolic inhibitors like ranolazine could potentially re-activate the immune cells to restore and enhance cellular-mediated antitumor immunity and tumor regression.”
Targeting Fat Oxidation in Mouse Prostate Cancer Decreases Tumor Growth and Stimulates Anti-Cancer Immunity
by Amanda Guth 1, Emily Monk 2ORCID, Rajesh Agarwal 3, Bryan C. Bergman 4, Karin A. Zemski-Berry 4, Angela Minic 5ORCID, Kimberly Jordan 5 and Isabel R. Schlaepfer 2,*ORCID 1
Department of Clinical Sciences, Flint Animal Cancer Center, Colorado State University, Fort Collins, CO 80523, USA 2
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA 3
School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA 4
Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA 5
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Int. J. Mol. Sci. 2020, 21(24), 9660; doi.org/10.3390/ijms21249660
Submission received: 19 November 2020 / Revised: 12 December 2020 / Accepted: 15 December 2020 / Published: 18 December 2020
Abstract
Lipid catabolism represents an Achilles heel in prostate cancer (PCa) that can be exploited for therapy. CPT1A regulates the entry of fatty acids into the mitochondria for beta-oxidation and its inhibition has been shown to decrease PCa growth. In this study, we examined the pharmacological blockade of lipid oxidation with ranolazine in TRAMPC1 PCa models. Oral administration of ranolazine (100 mg/Kg for 21 days) resulted in decreased tumor CD8+ T-cells Tim3 content, increased macrophages, and decreased blood myeloid immunosuppressive monocytes. Using multispectral staining, drug treatments increased infiltration of CD8+ T-cells and dendritic cells compared to vehicle. Functional studies with spleen cells of drug-treated tumors co-cultured with TRAMPC1 cells showed increased ex vivo T-cell cytotoxic activity, suggesting an anti-tumoral response. Lastly, a decrease in CD4+ and CD8+ T-cells expressing PD1 was observed when exhausted spleen cells were incubated with TRAMPC1 Cpt1a-KD compared to the control cells. These data indicated that genetically blocking the ability of the tumor cells to oxidize lipid can change the activation status of the neighboring T-cells. This study provides new knowledge of the role of lipid catabolism in the intercommunication of tumor and immune cells, which can be extrapolated to other cancers with high CPT1A expression.
Keywords: CPT1A; prostate cancer; acyl-carnitines; ranolazine; CD8 T-cells; dendritic cells; lipid metabolism