For locally advanced and metastatic gastroesophageal cancers, treatment options are limited. Preliminary data showed that ICIs in metastatic gastroesophageal cancer have demonstrated response rates of approximately 22%–27% for the subset of patients with PD-L1+ tumors (40%) and response rates of approximately 10%–17% for unselected patients. Therefore, investigating predictive biomarkers of ICIs is important to identify the target population that derives the best therapeutic benefit. Tumor suppressor gene neurofibromin 1 (NF1) encodes neurofibromin 1 protein, which negatively regulates the RAS/MAPK pathway. Targeting neurofibromin 1-regulated pathways offers potential therapeutic options for the treatment of tumors. However, its role in gastroesophageal cancer immunotherapy remains unknown. Here we aimed to demonstrate the association between NF1 and ICIs.
158 patients from two public immunotherapy cohorts (Janjigian 2017 and Samstein 2019 cohort) were included to analyze the association between NF1 gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of gastroesophageal cancer patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity.
In immunotherapy cohort, patients with NF1 mutation were significantly associated with better OS (HR = 0.23; P = 0.04) compared with those with wide-type. NF1 mutation were associated with increased TMB (P = 0.003). In TCGA, no association between NF1 mutation and OS was observed, suggesting that NF1 mutation may be a predictive but not a prognostic factor in ICI for gastroesophageal cancer. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, NF1 mutation was significantly associated with higher NK cells, and M1 macrophages. Moreover, NF1 mutation was associated with increased TMB (P = 0.02) in TCGA. In addition, GSEA analysis revealed that NF1 mutation was correlated with upregulated DDR signaling pathway in gastroesophageal cancer.
Our results demonstrated that NF1 mutation is an independent classifier that could stratify patients with gastroesophageal cancer for ICIs. The role of NF1 in immunotherapy is needed to be further studied.
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All authors have declared no conflicts of interest.