HMOX1 pathway signature predicts clinical benefit from immunotherapy plus tyrosine kinase inhibitor therapy in advanced renal cell carcinoma

Abstract

Background: Immunotherapy (IO) plus tyrosine kinase inhibitor (TKI) emerged as standard first-line therapy for advanced renal cell carcinoma (RCC). The heme Oxygenase 1 (HMOX1) pathway is involved in tumor development and treatment resistance, which may affect the efficacy of TKI + IO.

Methods: Two cohorts from our center (ZS-MRCC, ZS-HRRCC), one cohort from clinical trial (JAVELIN Renal 101) and the Cancer Genome Atlas (TCGA-KIRC) were enrolled. HMOX1 pathway signatures were determined for each sample by RNA-sequencing and gene set enrichment analysis. Immune infiltration was evaluated by flow cytometry. Response and progression-free survival (PFS) were set as primary endpoints.

Results: Patients of low-HMOX1 signature showed higher objective response rate (43.5% vs. 27.3%) in ZS-MRCC cohort and longer PFS in both cohorts (ZS-MRCC cohort, p = 0.019; JAVELIN-101 cohort, p = 0.036). Patients in the high-HMOX1 signature arm also showed greater clinical benefit from TKI + IO, rather than TKI monotherapy (p < 0.001). In high-HMOX1 signature RCC tissues, CD8⁺ T cells showed a dysfunctional phenotype with decreased GZMB expression (Spearman's ρ = -0.32, p = 0.045). A risk score based on HMOX1 signature was further constructed by random forest approach, involving HMOX1 signature and immunologic features. In patients with a low risk level, TKI + IO combination therapy demonstrated longer PFS than TKI monotherapy (p < 0.001), however in individuals with a high risk score group, these two regimens did not give different advantages.

Conclusions: Our study identified the HMOX1 pathway signature was a potential prognostic factor of progression-free survival for TKI + IO combination therapy in the advanced RCC in different cohort, especially in first-line management of mRCC in the Javelin 101 cohort. Moreover, HMOX1 signature was associated with T-cell function in tumor environment.

Keywords: T-cell dysfunction; heme oxygenase 1; immune checkpoint inhibitor; renal cell carcinoma; tyrosine kinase inhibitor.