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The monoclonal antibody αPD-1 used in immune checkpoint blockade (ICB) therapy has made a substantial impact in clinical outcomes for melanoma, lung, and breast cancer patients. Despite the success of ICB in these contexts, such strategies are not universally effective due to unresponsiveness or development of resistance by the malignant cells. Poor understanding of the molecular mechanisms leading to ICB resistance is a crucial barrier to more effective ICB. Recent studies have demonstrated that the metabolic milieu of the tumor microenvironment (TME) can modulate the anti-tumor immune response. However, the specific mechanisms by which the secretion of cancer cell metabolites into the TME impacts the efficacy of ICB in unresponsive tumors remains poorly understood. To better characterize the factors that influence ICB, we utilized a murine model (Smad4−/−/Pten−/−/Trp53−/−) of castration-resistant prostate cancer (CRPC) that is responsive to αPD-1. Serial culture and passage of residual tumor cells following exposure to αPD-1 treatment into new recipient mice allowed us to develop an ICB-insensitive CRPC cell line. Unbiased metabolic analysis revealed that the αPD-1 resistant cells produced elevated levels of itaconate, a metabolite whose biological functions in epithelial cells remain poorly characterized. Consistent with this finding, the resistant cells display increased expression of aconitate decarboxylase 1 (Acod1), the enzyme responsible for itaconate production. Additionally, we have identified established human epithelial cancer cell lines which express high levels of ACOD1. Interestingly, conditioned media (CM) from the Acod1-high cell lines, but not the Acod1-low lines, restricts the proliferation and activation of naïve CD8+ T cells in vitro. CRISPR-mediated Acod1 reduction in the αPD-1 insensitive cells (Acod1KO) produces CM which promotes increased naïve CD8+ T proliferation and activation, suggesting a link between Acod1 abundance in cancer cells and the activity of cytotoxic T cells. Furthermore, Acod1KO tumors have increased CD8+ tumor infiltrating lymphocytes (TILs) and increased sensitivity towards αPD-1 ICB in vivo. Taken together, these data suggest that cancer cell intrinsic ACOD1 abundance may be predictive of ICB efficacy. Citation Format: James H. Schofield, Joseph Longo, Sean Murphy, Ryan Sheldon, Mark A. Hawk, Emma Albano, Russell G. Jones, Xin Lu, Zachary T. Schafer. Enhanced Acod1 expression in cancer cells promotes immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6046. |
