NOTCH4 mutation as a potential predictive biomarker for immunotherapy in NRAS wildtype melanoma.

Abstract

e21594 Background: NRAS wildtype melanoma account for 80-85% melanoma patients and have been reported had a better response for immunotherapy. Although PD-L1 expression and tumor mutation burden (TMB) have been considered as important biomarkers for immunotherapy in many types of tumors, the predictive efficacy of them in melanoma is controversial. Since evidences showed NOTCH pathway mutation was a potential predictive biomarker for immune checkpoint inhibitors in some types of tumors. Here we explored the relationship between NOTCH family genes mutations and efficacy of NRAS wildtype melanoma immunotherapy. Methods: 265 NRAS wildtype ICI-pretreatment melanomas from cBioPortal (https://www.cbioportal.org), which is divided to discovery (N = 76) and validation (N = 189) cohort to analyze the association between NOTCH family genes (NOTCH1-4) mutation and efficacy of ICIs therapy. All nonsynonymous somatic mutations, including nonsense, missense, nonstop, frameshift deletion and insertion, in-frame deletion and insertion, and splice site mutations were considered for inclusion in our study. The potential mechanism was subsequently explored through RNA expression in immunotherapy treated population. Results: Patients with NOTCH4-Mut were identified to be associated with prolonged overall survival (OS) in discovery (HR: 0.30, 95%CI: 0.11-0.83, P = 0.01) and validation cohort (HR: 0.21, 95%CI: 0.07-0.68, P = 0.003). Further exploration found that NOTCH4-Mut tumors had higher tumor mutation burden (TMB) and tumor neoantigen burden (TNB) (P < 0.05). RNA data revealed that enhanced anti-tumor immunity was observed in NOTCH4-Mut tumors. Activated CD4 memory T cell, CD8 T cell, follicular helper T cell (Tfh) and Neutrophils were more abundant in NOTCH4-Mut tumors. In addition, the results of enrichment analysis showed that several immune-related pathways varied significantly between NOTCH4-Mut and NOTCH4-Wt tumors, including Interferon γ response, DNA repair, epithelial mesenchymal transition (EMT), angiogenesis. Conclusions: NOTCH4 mutation may promote tumor immunity and serve as a biomarker to predict good immune response in NRAS wildtype melanoma and guiding immunotherapeutic responsiveness.