AUTHOR=Li Hongxia , Zhang Qin , Duan Qianqian , Tan Yuan , Sun Tingting , Qi Chuang 

TITLE=NOTCH4 mutation as predictive biomarker for immunotherapy benefits in NRAS wildtype melanoma

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.894110

DOI=10.3389/fimmu.2022.894110

ISSN=1664-3224

ABSTRACT=Background: NRAS wildtype melanoma accounts for approximately 80% of melanomas.  Previous studies have shown that NRAS wildtype melanoma had higher response rates and better prognoses than NRAS-mutant patients following immunotherapy. While as major actors in tumor cells and tumor microenvironment (TME), the association between NOTCH family genes and response to immune checkpoint inhibitors (ICIs) in NRAS wildtype melanoma remains unclear. 
Objective: We aim to explore whether NOTCH family genes mutation is associated with genomic factors in ICIs response in NRAS wildtype melanoma and with clinical outcomes in ICI-treated patients.
Method: This study used multidimensional genomic data of 265 NRAS wildtype ICI-pretreatment samples from five ICI-treated melanoma cohorts to analyze the association between NOTCH family genes mutation and efficacy of ICIs therapy. 
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). Moreover, NOTCH4-Mut melanoma had a superior clinical response in discovery cohort (ORR, 40.0% vs 13.11%, P = 0.057) and validation cohort (ORR, 68.75% vs 30.07%, P = 0.004). Further exploration found that NOTCH4-Mut tumors had higher tumor mutation burden (TMB) and tumor neoantigen burden (TNB) (P < 0.05). And NOTCH4-Mut tumors had a significant increased mutations in DNA damage response (DDR) pathway. Gene set enrichment analysis revealed NOTCH4-Mut tumor enhanced anti-tumor immunity. 
Conclusion: NOTCH4 mutation may promote tumor immunity and serve as a biomarker to predict good immune response in NRAS wildtype melanoma and guiding immunotherapeutic responsiveness.