3251 - Development of a Radioimmunotherapy Score for Identifying SBRT-Treated Renal Cell Carcinoma Patients Eligible for Immunotherapy

Purpose/Objective(s): Traditional methods for predicting responses to immunotherapy in renal cell carcinoma (RCC), such as the PD-L1 tumor proportion score, often fail to account for radiotherapy-induced effects and cellular heterogeneity, limiting their predictive accuracy. This study aimed to utilize single-cell RNA sequencing (scRNA-seq) data from stereotactic body radiotherapy (SBRT)-treated RCC to develop a radioimmunotherapy (RIT) score that captures SBRT-specific immune changes, enabling precise and dynamic prediction of responses to combined SBRT and immunotherapy.

Materials/Methods: We analyzed scRNA-seq data from four RCC samples following SBRT, along with two control samples. Immune checkpoint expression was assessed post-SBRT, and immune cell populations with significantly upregulated checkpoint expression were identified. These populations were then used to construct the RIT score. The score was further evaluated using bulk RNA-seq data from 525 RCC patients, comparing immune response scores between high- and low-RIT score groups. Additionally, the RIT score was validated in an RCC immunotherapy cohort comprising 311 patients to assess its predictive value for immunotherapy outcomes.

Results: We focused on the expression changes of key immune checkpoint genes, including PDCD1, HAVCR2, CTLA4, LAG3, CD47, VSIR, TIGIT, and CD276, across immune cell subsets following SBRT. Immune checkpoint expression was upregulated in all immune cell populations post-SBRT. Notably, CXCL13⁺ CD8⁺ T cells and CLEC9A⁺ dendritic cells (DCs) exhibited higher expression levels. Specifically, CXCL13⁺ CD8⁺ T cells showed significantly elevated HAVCR2 and LAG3 expression, while CLEC9A⁺ DCs exhibited the most pronounced upregulation of HAVCR2, CD47, and VSIR. Based on these findings, we constructed the RIT score, which effectively stratified RCC patients. Patients with high RIT scores demonstrated significantly higher immune response scores than those with low scores. Additionally, high-RIT-score patients showed improved survival in the immunotherapy cohort.

Conclusion: This study demonstrates that SBRT significantly modulates immune checkpoint expression in RCC, with CXCL13⁺ CD8⁺ T cells and CLEC9A⁺ DCs playing critical roles in this response. The RIT score effectively identifies patients with heightened immune responsiveness, making it a promising tool for predicting patients most likely to benefit from combined SBRT and immunotherapy.