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IP84-15 ENRICHED YES1 TUMOR EXPRESSION AT THE STROMAL INTERFACE IS ASSOCIATED WITH WORSE OVERALL SURVIVAL IN CLEAR CELL RENAL CELL CARCINOMA WHEN TREATED WITH FIRST-LINE IMMUNE CHECKPOINT BLOCKADE
Abstract   Peer reviewed

IP84-15 ENRICHED YES1 TUMOR EXPRESSION AT THE STROMAL INTERFACE IS ASSOCIATED WITH WORSE OVERALL SURVIVAL IN CLEAR CELL RENAL CELL CARCINOMA WHEN TREATED WITH FIRST-LINE IMMUNE CHECKPOINT BLOCKADE

Alyssa Obermayer, Alex Soupir, Carlos Moran-Segura, Paola Ramos Echevarria, Liz Darst, Doug Marchion, Sean Yoder, Jodi Balasi, Michelle Churchman, Eric Singer, …
The Journal of urology, Vol.215(5S), p.e1652
05/2026
DOI: 10.1097/01.JU.0001191780.77127.c5.15

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Abstract

INTRODUCTION AND OBJECTIVES: Most patients with advanced clear cell renal cell carcinoma (ccRCC) will develop resistance to immune checkpoint blockade (ICB) on therapy. SRC-family gene YES1 is upregulated in malignant cells at the stromal interface of treatment resistant primary tumors. Our objective was to develop a bulk RNA sequencing (RNAseq) gene signature based on spatial single cell transcriptomic (scST) expression of YES1 and test for overall survival (OS) in the Oncology Research Information Exchange Network’s (ORIEN) multiinstitutional molecular database of patients treated with ICB. METHODS: Tissue microarrays were constructed using one-millimeter cores from the stromal interface of surgically excised primary ccRCC tumors and normal controls. scST was obtained using a 6,000 gene panel. Malignant cell YES1 expression was compared between treatment naïve and treatment exposed samples. Genes of known related proteins to YES1 were tested for correlation within tumor cells and between groups. Same patient RNAseq data were used to construct a signature based on malignant YES1 expression. We tested OS in treatment naive patients with a metastatic diagnosis who received any systemic therapy and a subgroup of patients who received first line ICB in the ORIEN cohort. Rank sum test and cox regression were performed. RESULTS: 209,255 cells were analyzed from 21 treatment-naïve and 11 treatment-exposed patients. On linear mixed effect modeling, YES1 expression was higher in ICB exposed patients but not TKI exposed patients (p=0.001 and p=0.634). In ORIEN, significantly elevated YES1 score was associated with worse OS in 130 patients with treatment naïve metastatic ccRCC who received systemic therapy (p-value 0.047). In 69 patients who received first line ICB, elevated YES1 score was associated with worse OS (p=0.019), but not in the 69 patients who received first line TKI therapy (p=0.296). Seven known YES1-related genes were correlated within tumor cells and expressed at higher levels within ICB-exposed patients in both the single-cell and bulk RNA sequencing data (GRB2, CRK, PAK2, MAPK1, NCK1, MAPK14, and NRAS). CONCLUSIONS: A spatially informed bulk RNA gene signature associated with malignant cell YES1 upregulation at the stromal interface was associated with worse OS in a cohort of patients who received first line ICB treatment.

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