Abstract PR016: Functional loss of actin-regulatory protein Profilin1 in vascular endothelial cells promotes a T-cell supportive chemical milieu in kidney cancer in a TRIM24-dependent manner

Abstract Background. Transcriptional upregulation of actin-binding protein Profilin-1 (Pfn1) is associated with adverse disease outcome in human clear cell renal cell carcinoma (ccRCC). Our previous studies found that Pfn1 is predominantly upregulated in tumor-associated vascular endothelial cells (ECs). Mouse model studies and clinical correlative analyses further established a direct causal relationship between EC Pfn1 dysregulation, tumor immune microenvironment modulation, and disease progression in RCC. The goal of this study is to gain mechanistic insights into how endothelial Pfn1’s action negatively regulates T cell trafficking into RCC tumors. Results. We performed studies utilizing an hTERT-immortalized murine kidney EC line harboring floxed Pfn1 alleles to first demonstrate that genetic loss of Pfn1 function in kidney ECs promotes chemotactic migration of both CD4 and CD8 T cells via transcriptionally upregulating T-cell recruiting chemokines (CCL5 and CXCL10) through increased activation of pro-inflammatory NFkb and STAT1/Interferon signaling. By upstream regulator analyses of transcriptomic data of murine RCC tumor samples as well as cultured ECs, we further identified tripartite-motif containing-24 (TRIM24), a dual-function ubiquitin-ligase/transcriptional modulator, to be robustly functionally inhibited in the absence of Pfn1 expression in ECs. Triggering functional loss of TRIM24 by either a selective bifunctional degrader or a small molecule inhibitor phenocopies the pro-inflammatory signatures of Pfn1-deficient ECs. We further established two divergent TRIM24-regulated downstream signaling axes, namely mitochondrial ROS-driven activation of p38MAPK/NFKb and retinoic acid receptor (RAR)-dependent STAT1 modulation, that link EC-Pfn1’s loss to stimulation of CCL5/CXCL10-driven chemotactic migration of T cells. Conclusions. These findings suggest that TRIM24 plays a central role in endothelial Pfn1-dependent control of chemical milieu for T-cell trafficking, and therefore Pfn1–TRIM24 axis may represent a novel therapeutic target for modulating inflammatory responses in vascular tissues and RCC tumor microenvironment. Citation Format: Sudeep Kumar. Maurya, Grace Tuan, Ananya Shetty, David Gau, Partha Roy. Functional loss of actin-regulatory protein Profilin1 in vascular endothelial cells promotes a T-cell supportive chemical milieu in kidney cancer in a TRIM24-dependent manner [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr PR016.