BMC Urology (Jan 2024)
RUNX3 pathway signature predicts clinical benefits of immune checkpoint inhibition plus tyrosine kinase inhibition in advanced renal cell carcinoma
Abstract
Abstract Background Checkpoint inhibitor immunotherapy plus tyrosine kinase inhibitor (IO/TKI) have been recently recommended as standard first-line therapy for advanced renal cell carcinoma, while no clinical-available biomarker has been applied. This study aimed to investigate the associations between RUNX3 pathway signature and IO/TKI benefits in renal cell carcinoma (RCC). Methods Two IO/TKI cohorts (ZS-MRCC, JAVELIN-101) and one high-risk localized RCC cohort (ZS-HRRCC) were included. All samples were evaluated by RNA-sequencing, and RUNX Family Transcription Factor 3 (RUNX3) pathway were determined by single sample gene set enrichment analysis. Flow cytometry were applied for immune cell infiltration and function. Results RUNX3 signature was elevated in RCC samples, compared non-tumor tissues (P < 0.001). High-RUNX3 signature was associated with shorter progression-free survival (PFS) in both IO/TKI cohorts (ZS-MRCC cohort, P = 0.025; JAVELIN-101 cohort, P = 0.019). RUNX3 signature also predicted IO/TKI benefit in advanced RCC, compared with TKI monotherapy (interaction p = 0.027). RUNX3 signature was associated with decreased number of GZMB + CD8 + T cells (Spearman’s ρ=-0.42, P = 0.006), and increased number of PD1 + CD8 + T cells (Spearman’s ρ = 0.29, P = 0.072). Moreover, the integration of RUNX3 signature and GZMB expression showed predictive potential for TKI/IO (log-rank P < 0.001). In addition, the predictive value of RUNX3 signature for IO/TKI benefit was restricted in SETD2-wild type patients (log-rank P < 0.001). Finally, a risk score was established by random forest for IO/TKI benefit, showing remarkable predictive potency (Log-rank P < 0.001). Conclusions RUNX3 pathway signature could be a potential predictive biomarker for IO/TKI treatment in advanced RCC, for both prognosis and treatment selection between IO/TKI and TKI monotherapy.
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