Abstract The lens epithelium derived growth factor p75 (LEDGF/p75), encoded by the PSIP1 gene, is a stress oncoprotein that contributes to cancer chemoresistance and tumor aggressiveness through its ability to tether oncogenic transcription factors to active chromatin, promote RNA-loop resolution at transcriptionally active sites, enhance DNA repair, and maintain genomic integrity. Its depletion in prostate cancer (PCa) cells induces genomic instability, which may result in the upregulation of inflammatory gene pathways. LEDGF/p75, also known as the DFS70 nuclear autoantigen, triggers IgG autoantibodies in subsets of healthy individuals, patients with miscellaneous inflammatory conditions, and PCa patients. These autoantibodies have been shown to be associated with lower circulating levels of inflammatory markers. Our recent studies also demonstrated that LEDGF/p75 is upregulated in docetaxel (DTX)-resistant PCa cells and contributes to chemoresistance by regulating gene pathways associated with stress survival, DNA repair, and cell cycle progression. We hypothesized that its silencing in chemoresistant PCa cells may also alter immune-related gene pathways. Knockdown of LEDGF/p75 in chemoresistant PCa cells followed by RNA-seq analysis led to the identification of 970 differentially expressed genes (DEGs). Gene set enrichment analysis (GSEA) revealed a role for LEDGF/p75 in modulating gene pathways associated with lymphocyte and inflammatory responses, since its downregulation led to upregulation of several inflammation-related genes including IL7R, IL18, SWAP70, BMI-1, ULBPI/2, RAET1E/L, TRPM4, FADD, and several MHC class I genes. This suggested that high LEDGF/p75 expression, known to be associated with genomic integrity, may suppress inflammatory responses. Protein expression of these genes was validated by Western blotting in PCa cells with high/low LEDGF/p75 expression. High expression of most of these inflammatory genes also correlated with better overall survival of cancer patients receiving PD-L1, PD-1, or CTLA-4 immunotherapy, as revealed by KM Plotter-Immunotherapy analysis. In addition, publicly available RNA-seq data for various immune cells revealed potential roles of LEDGF/p75 in promoting CD4 and CD8 T cell activation. Further, public scRNA-seq data pointed to LEDGF/p75 expression in T cell clusters for various cancer types. We conclude that as a guardian of genome integrity, LEDGF/p75 contributes to the negative regulation of inflammatory gene pathways. Understanding LEDGF/p75’s roles in cancer immunity and cancer-related autoimmunity may provide new insights into its immunomodulatory functions and its influence on cancer patient response to immunotherapy. Citation Format: Pedro T. Ochoa, Evelyn S. Sanchez-Hernandez, Adelaide Makamure, Janani Nagasubramanya, Sharan Bir, Kai Wen Cheng, Zhong Chen, Issac Kremsky, Charles Wang, Carlos A. Casiano. Novel roles of the nuclear autoantigen LEDGF/p75 in modulating prostate cancer related inflammatory pathways and cancer patient response to immunotherapy abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr A009.
Ochoa et al. (Wed,) studied this question.