1911P - Effect of VHL mutations on efficacy of immune checkpoint inhibitors in renal cell carcinoma

Background

Mutations of the von Hippel-Lindau (VHL) tumor suppressor gene occur in the majority of sporadic renal-cell carcinomas (RCC). Certain VHL mutations correlate with low expression of classical HLA-I molecules and HLA-E expression that determine higher NK susceptibility. Therefore, VHL mutation maybe a predictor of responses to immune checkpoint inhibitors (ICIs). Our research aims to elucidate its mutation association with ICI efficacy.

Methods

In order to investigate the correlation between VHL mutation and ICI efficacy in the RCC, we used cBioportal to collect clinical and mutation data of 151 ICI-treated RCCs from MSKCC cohort. Gene expression and WES data of 313 samples were obtained from the TCGA database for further analysis of potential biological mechanisms between VHL-mutant and VHL-wildtype tumors. Tumor mutation burden (TMB) was calculated as the total number of somatic non-synonymous mutations per megabase in both MSKCC and TCGA cohorts. CIBERSORT algorithm was applied to infer 22 human immune cell type proportions in TCGA RCCs.

Results

In the MSKCC immunotherapy cohort, we observed 70.2% (106/151) patients harbored VHL mutation, while TCGA had lower mutation frequency with 50.5% (158/313). As indicated by Kaplan-Meier analysis, the patients with VHL mutation had significantly better OS in the MSKCC cohort (P < 0.001, median OS: 50 months vs 26 months). This link was still existing when controlling for age, sex, ICI types, TMB and metastasis in the multivariate Cox regression analysis (P = 0.005, HR = 0.45, 95%CI = 0.26-0.78). As expected, the VHL-mutant group had higher TMB than that of the VHL-wildtype group in both the MSKCC cohort (P <0.001) and TCGA cohort (P = 0.047). Immune cell analysis showed that CD8+ T cells, CD4 naïve T cells, T follicular helper cells and Macrophage M1 cells were abundant in the VHL-mutant group (both P < 0.05). These results indicated VHL-mutant tumors had an activated antitumor immune microenvironment.

Conclusions

VHL mutations might be a potential biomarker to predict the efficacy of immunotherapy for RCC. Considering the heterogeneity among the patients and other confounding factors, further prospective validation cohorts are warranted.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.