Abstract A021: CPT1A-mediated fat oxidation and its role in the immune response to prostate cancer

Background and Rationale: While impressive improvements in immunology have led to the identification of immune checkpoint proteins such as CTLA-4 and PD-1/PD-L1 that trigger inhibitory T cell antitumor activity, these methods do not work well in PCa patients, underscoring the need to devise novel, safe ways to stimulate the immune system to attack tumors. Recent data shows that PCa tumors use lipid to grow and secrete signals that inactivate the immune cells, so they cannot expand, activate, and attack the tumors. Specifically, activation of lipid oxidation via CPT1A in T cells leads to decreased expansion and anticancer action, suggesting that blocking the ability of tumor and infiltrated T cells to burn lipid will likely stimulate the immune system. Our study goal was to study systemic therapies in mice that block the ability of cells to burn lipid in a safe, nontoxic manner but with significant anticancer effects. Experimental Approach: In order to study the role of the immune system, we used TRAMPC1 cells, a mouse PCa cell line that is syngeneic with C57BL/6 mice and grows well in allografts. Additionally, we generated Cpt1a Knockdown (KD) TRAMPC1 cells and cocultured them with mouse splenocytes to investigate the role of cytokines in the tumor-immune cell. We used etomoxir and perhexiline as inhibitors of CPT1. Ranolazine, an FDA-approved partial fat oxidation inhibitor, was also used in the studies. Infiltrating tumor T-cell phenotypes were examined by flow cytometry and immunofluorescence, staining for CD3, CD4, CD8, T-cell checkpoint molecules PD-1. Results: In order to study the role of the immune system, we used TRAMPC1 PCa cells, which we have found to express abundant Cpt1a and have been used successfully for PCa studies We have found that TRAMPC1 cells are sensitive to treatments with fat oxidation inhibitors (ranolazine, etomoxir, and perhexiline), resulting in a decrease of colony growth over 14 days (50% decrease in growth, p Conclusions: The inability to mount an efficient immune response that restricts cancer progression is partially due to the presence of nonactive effector T cells present in tumors. Our results indicate that PCa tumors use lipid to grow and secrete signals that inactivate the immune cells, so they cannot expand and attack tumors. Concomitantly, activation of lipid oxidation in T cells leads to decreased expansion and anticancer action, suggesting that blocking both, the ability of tumors and infiltrated T cells to burn lipid, will likely stimulate the immune system to reduce tumor burden. Thus, nontoxic strategies that modify the lipid bioenergetics of immune cells and/or tumor cells themselves offer strong potential to improve or synergize with other forms of therapy, and increase the efficacy of treatments against PCa. Citation Format: Amanda M. Guth, Maren Salzmann-Sullivan, Camille Beaton, Amir Goldkorn, Emily A. Gibson, Elizabeth Kessler, Elaine Lam, Thomas Flaig, Rajesh Agarwal, Isabel R. Schlaepfer. CPT1A-mediated fat oxidation and its role in the immune response to prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A021.