#0854

PRMT2/RIPK3/MLKL Axis Regulates CXCL5 Secretion to Suppress MDSC Recruitment in Prostate Cancer

X. Zhang¹, L. Mao¹, H. Guo¹, J. Zhuang¹

¹Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Department of Urology, Nanjing, China

Introduction:

Introduction & Objectives: Prostate cancer is the fourth most common malignancy globally and a leading cause of mortality among men. Classified as an immune-cold tumor, prostate cancer is characterized by a high prevalence of myeloid-derived suppressor cells (MDSCs) within its tumor microenvironment. MDSCs, a unique subset of myeloid regulatory cells, play a pivotal role in dampening adaptive immune responses, particularly by suppressing T-cell-mediated anti-tumor activity through various mechanisms, thereby contributing to immune suppression in the tumor setting. This immune-cold nature of prostate cancer presents challenges to effective immunotherapy. The mechanisms driving MDSC recruitment in prostate cancer are still not fully understood. Our study aims to investigate novel mechanisms of MDSC recruitment in prostate cancer to inform the development of new immunotherapeutic strategies

Material and methods:

Immunohistochemistry on human prostate cancer tissues was performed to evaluate the association between PRMT2 and prostate cancer. A lentiviral system was used to generate PRMT2-overexpressing RM1 cell models, and a subcutaneous tumor model was established in C57BL/6 mice. Immune cell subsets within the tumor microenvironment were profiled using flow cytometry. To explore PRMT2-regulated downstream genes, CUT&Tag, RNA sequencing, Western blot, and qPCR analyses were performed on RM1, PC-3, and 22RV1 cells. The efficacy of anti-PD1 therapy was then evaluated in the C57BL/6 subcutaneous tumor model.

Results:

Immunohistochemical analysis of human prostate cancer tissues revealed that PRMT2 expression levels were positively correlated with the proportion of CD4 and CD8 T cells and inversely correlated with the proportion of MDSCs. Immune cell profiling of the subcutaneous tumor model with PRMT2-overexpressing RM1 cells showed a significant increase in PMN-MDSCs. RNA sequencing indicated marked downregulation of the RIPK3 gene. CUT&Tag analysis demonstrated PRMT2-associated histone modification binding at the RIPK3 promoter. Western blot and qPCR analyses confirmed that PRMT2 overexpression downregulated both RIPK3 and MLKL, with a concurrent significant decrease in CXCL5 expression. In vivo experiments further showed that PRMT2 overexpression enhanced the efficacy of PD-1 monoclonal antibody treatment.