Abstract A032: Elevated <i>RAD21</i> levels promote immune evasion in prostatic malignancies

Abstract Genomic copy number alterations cause aneuploidy, a hallmark of cancer characterized by imbalanced chromosome numbers. Aneuploidy has been shown to negatively associate with cancer immune signaling, but these mechanisms remain understudied. Of note, high levels of aneuploidy are strongly correlated with lethal progression and poor patient outcomes in prostate cancer. Our recent work identified chromosome 8q (chr8q) gain, one of the most frequent aneuploidy events in prostate tumors, as a key driver of disease progression, in part through the cohesin RAD21 gene located on the chr8q24 region. In both prostate cell line and organoid models, we demonstrated that increased RAD21 expression accelerates oncogenesis and aggressive tumor proliferation by mitigating cellular stress during early-stage tumorigenesis. Therefore, we hypothesize that elevated RAD21 levels enable cancer cells to evade immune surveillance by alleviating oncogenic stress and DNA damage. In this study, we analyzed publicly available genomic datasets and discovered that higher RAD21 expression negatively correlated with natural killer (NK) cell infiltration in prostate tumors. To further test our hypothesis, we modulated RAD21 levels in isogenic prostate cell culture models. Using an NK cell co-culture assay, we observed that cells with increased RAD21 expression were significantly less susceptible to NK-mediated cytotoxicity and exhibited greater survivorship when co-cultured with NK cells. In addition, we found that cellular levels of various pro-inflammatory cytokines, including those that stimulate NK cell activation, were significantly downregulated when RAD21 was overexpressed. These findings are consistent with our observation that tumors with high RAD21 levels are linked to reduced NK cell infiltration in prostate cancer cases. Our results suggest that amplification of RAD21, commonly associated with chr8q gains, facilitates immune evasion in cancer cells, thereby promoting early-stage oncogenesis. Targeting RAD21-driven immune evasion may reveal novel therapeutic strategies to restore immune surveillance mechanisms in prostate cancer. Citation Format: Elise G. DeArment, Faith Kim, Ruoxi W. Wang, Kate Lu, John R. Lozada, Christine Luo, Andrew Elliott4, Nicholas A. Zorko3, Justin H. Hwang3, David Takeda5, Xiaofeng A. Su. Elevated RAD21 levels promote immune evasion in prostatic malignancies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A032.