MON-504 Investigating the Immunomodulatory Role of wnt5a in Adrenocortical Carcinoma

Abstract Disclosure: Y. Imodoye: None. K. Warde: None. G. Castaneda-Hernandez: None. L. Smith: None. K. Basham: None. Adrenocortical carcinoma (ACC) is a rare, but aggressive malignancy that develops in the adrenal cortex. ACC carries a poor prognosis, with an overall five-year survival rate <50%. The current standard of care, mitotane, is largely ineffective, as many patients continue to progress on treatment, highlighting the urgent need for more effective therapeutic strategies. Despite their success in many solid tumors, T cell-focused immunotherapies have shown limited efficacy in ACC, suggesting the need to explore alternative immune pathways. Myeloid cells, including macrophages and dendritic cells, often dominate the tumor microenvironment, where they can either promote or inhibit tumor growth. Insights from human data and mouse models suggest a potential anti-tumor role of myeloid cells in ACC. This myeloid response is characterized by the high phagocytic activity of macrophages and dendritic cells, resulting in cell clearance and subsequent adrenal regression. However, the mechanisms governing the anti-tumor activity of myeloid cells in ACC remain unclear. In our previous studies using a novel mouse model of ACC based on loss of the tumor suppressor Znrf3, we observed Wnt5a upregulation in association with a poor myeloid response and increased tumorigenesis long-term. Conversely, Wnt5a downregulation correlated with a robust anti-tumor myeloid response and lower tumor incidence. WNT5A is a secreted glycoprotein of the Wnt signaling family, and its paracrine activity has been implicated in tumor progression by promoting myeloid-mediated immune tolerance. We hypothesize that loss of Wnt5a enhances the infiltration and anti-tumor activity of myeloid immune cells, resulting in reduced ACC tumorigenesis. To test our hypothesis, we generated Znrf3 conditional knockout (cKO) and Znrf3;Wnt5a double knockout (dKO) mouse models. We found that loss of Wnt5a enhanced the intra-adrenal myeloid immune response and promoted adrenal regression. Preliminary data from long-term tumor monitoring also revealed increased tumor-free survival in dKO compared to cKO animals. Strikingly, in human tumors, data from The Cancer Genome Atlas (TCGA) showed that low WNT5A expression correlated with favorable overall survival and enhanced anti-tumor myeloid immune functions. Collectively, insights from our mouse model and clinical data have unveiled WNT5A as a potential oncogenic driver of ACC through myeloid immune modulation. Additional experiments will elucidate the mechanisms through which WNT5A regulates the anti-tumor myeloid response. Given the limited efficacy of existing treatments for ACC, these findings provide a strong rationale for the development of WNT5A antagonists in combination with myeloid-based immunotherapy as a novel therapeutic approach for this lethal disease. Presentation: Monday, July 14, 2025