Abstract A004: SRF promotes an immunopermissive microenvironment in sarcomatoid renal cell carcinoma

Abstract Although only observed in approximately 5% of cases of renal cell carcinoma, sarcomatoid features are correlated with the most aggressive tumors. However, more recently, it has been discovered that sRCCs are “super-responders” to immune therapies including immune checkpoint inhibitors with up to 50% of sRCCs showing significant response to treatment. Why some tumors respond while others do not is unknown. We previously reported that ablation of the serine/threonine kinases Lats1 and 2 (paralogs of the Drosophila growth regulator Warts) from adult kidney epithelium leads to metastatic sarcomatoid renal cell carcinoma (sRCC). To gain insight into how Lats1/2 ablation leads to sRCC, we transcriptionally profiled mutant cells/tumors. Bioinformatic analysis of our RNA-Seq data revealed that transcriptional targets of the serum response factor (SRF) were enriched in the Lats mutant transcriptome. To test the role of SRF in sRCC progression, we co-deleted the gene along with Lats1 and 2 from adult mouse kidney epithelia. Interestingly, we found that Srf deletion did not affect tumor initiation but did affect tumor progression. Analysis of triple mutants suggests that Srf activity is necessary to promote a tumor-permissive immune microenvironment. We are currently defining the cellular and molecular targets of SRF in sRCC progression. A greater understanding of the role of SRF in tumor immunity will promote our understanding of immune evasion and help to develop additional therapies to promote immune attack of RCC. Citation Format: Thomas J. Carroll. SRF promotes an immunopermissive microenvironment in sarcomatoid renal cell carcinoma [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 A004.