Background
Immunotherapy has been widely used in urothelial carcinoma (UC). Unfortunately, challenge remains in identification of biomarkers to select patients most likely to benefit. KDM6A, a lysine-specific demethylase, is frequently mutated in UC. Nevertheless, the underlying relationship between mutational status of KDM6A and immunotherapy is still elusive.
Methods
Our study included two cohorts. We collected 275 patients from IMvigor210, a phase 2 trial evaluated efficacy of atezolizumab in UC. Patients were divided into two groups: KDM6A wild (KDM6A-Wt) and KDM6A mutant (KDM6A-Mut) group. Survival analysis was constructed by Kaplan-Meier curves. Wilcoxon tests were performed to identify differences in TMB and chi-squared test was used in PD_L1 and ORR analysis. To further confirm the function of KDM6A, 272 patients with UC of stage III/IV were then obtained from TCGA. CIBERSOER was used to estimate the immune cell proportion in both two cohorts.
Results
In IMvigor210 cohort, patients in KDM6A-Mut group had a significantly prolonged overall survival (OS) than in KDM6A-Wt group (mOS: 12.85 vs. 8.05 months, P = 0.031, HR = 0.62, 95%CI: 0.41-0.96). TMB in KDM6A-Mut group was significantly higher than in KDM6A-Wt group (P = 0.033), and KDM6A-Mut group had a better ORR (P = 0.036). However, no significant difference was observed on PD_L1 between the two groups. Immune cell analysis showed that Eosinophils (P = 0.024), Macrophages.M1 (P = 0.027), Neutrophils (P = 0.011), NK activated cells (P = 0.026) was significant different between KDM6A Wild/Mut groups. Furthermore, in TCGA cohort, we also found a significant higher TMB (P = 0.041) in KDM6A-Mut group, and immune cell proportion was different in Eosinophils (P = 0.018), Macrophages.M1 (P = 0.017), B cells memory (P = 0.002), Dendritic.cells.activated (P = 0.032) between the two groups.
Conclusions
Our research revealed that patients with UC harboring KDM6A mutation had a better clinical outcomes of immunotherapy, indicating KDM6A mutation can be regarded as a potential immunotherapy biomarker in UC. Future researches should focus on the validation of the predictive value of KDM6A in prospective trials and more fundamental exploration of its molecular mechanism.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
