Abstract 2331: Metabolic evasion of mCRPC immunotherapy by ACOD1 production of itaconate

Abstract

Abstract The use of immune checkpoint blockade (ICB) therapies in the form of αPD-1 & αCTLA-4 monoclonal antibodies (mAb) have made great strides in the battle against melanoma, lung, and breast cancers. However, these strategies are not universally effective. Roadblocks occur as certain cancers cannot be targeted by these therapies or may develop resistance to ICB. How resistance to ICB therapy arises represents a crucial barrier to more effective use of these therapies. Recent studies have demonstrated that the metabolic milieu of the tumor microenvironment (TME) plays a role in regulating the anti-tumor immune response. However, the specific mechanisms by which cancer cell secreted metabolites in the TME impact the responsiveness of cancer cells to ICB remain poorly understood. In order to better understand the factors that influence the effectiveness of ICB, we utilized a mouse model (Smad4-/-/Pten-/-/Trp53-/-) of male castration resistant prostate cancer (mCRPC) that is responsive to αCTLA-4 and αPD-1 ICB. Using serial culture and injection of residual tumor cells that survive ICB, we generated cell lines that had developed resistance to ICB. Unbiased metabolomic screening of these cell lines revealed a stark increase in the production of the anti-inflammatory metabolite itaconate in the resistant cell lines. This observation was supported by the increased abundance of the enzyme responsible for itaconate production, aconitate decarboxylase 1 (ACOD1) among the resistant lines. Reduction of this enzyme through shRNA compromises the viability of ICB resistant cells but not sensitive cells. Interestingly, conditioned media from the resistant cell lines restricts the in vitro activation of naïve CD8+ T cells. Furthermore, the reduction of ACOD1 among the resistant population results in increased activation of CD8+ T cells when treated with conditioned media from these resistant cells. These observations also extend to other, more established cell lines like the Lewis lung carcinoma (LLC). Taken together, these results indicate that cancerous epithelial cell production of itaconate, through the activity of ACOD1, may represent a mechanism that antagonizes T cell activation and thus promotes ICB evasion. Citation Format: James H. Schofield, Mark A. Hawk, Sharif Rahmy, Ryan D. Sheldon, Casey Leimbach, Seunghoon Sun, Xin Lu, Russell G. Jones, Zachary T. Schafer. Metabolic evasion of mCRPC immunotherapy by ACOD1 production of itaconate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2331.