NOTCH3 is a Prognostic Factor and Is Correlated With Immune Tolerance in Gastric Cancer
Yuehong Cui, Qian Li, Wei Li, Yan Wang, Fang Lv, Xinying Shi, Zhaoqing Tang, Zhenbin Shen, Yingyong Hou, Henghui Zhang, Beibei Mao, Tianshu Liu
Abstract
INTRODUCTION: Although traditional treatments confer survival benefits to patients with gastric cancer (GC), many patients experience relapse soon after postoperative adjuvant therapy. Immune-related mechanisms play an important role in GC, and immunotherapeutic strategies are considered to be a promising direction for the treatment of GC. Thus, our study aimed to investigate the expression and prognostic significance of immune-related genes in GC. METHODS: Formalin-fixed, paraffin-embedded samples were collected from 48 resectable GC patients. The transcriptome data of the tumor immune microenvironment were assessed using an immuno-oncology 395-gene panel RNA sequencing platform. The prognostic value of the 395 genes was analyzed and validated in the KM plotter and GEPIA databases. The data from The Cancer Genome Atlas (TCGA, downloaded from UCSC Xena repository) and Tumor IMmune Estimation Resource (TIMER) were used to evaluate the correlations between prognostic factors and immune signatures. RESULTS: T cells and a higher infiltration of immunosuppressive cells including Tregs and M2 macrophages in the tumor microenvironment. Moreover, high NOTCH3 expression was accompanied by the increased expression of a series of immune checkpoint inhibitors, resulting in a dampened immune response. Interestingly, NOTCH3 expression had a negative association with well-documented predictive biomarkers of immune checkpoint blockade (ICB) immunotherapy, including tumor mutation burden (TMB), gene expression profiling (GEP) score and innate anti-PD-1 resistance (IPRES) signature. CONCLUSION: These findings uncovered a new mechanism by which NOTCH3 participates in the immune tolerance of GC, implying the potential of NOTCH3 as a therapeutic target or predictive marker for GC patients.