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Published on: January 12, 2020
NOTCH3 is a Prognostic Factor and Is Correlated With Immune Tolerance in Gastric Cancer
Yuehong Cui1, Qian Li1, Wei Li1
1Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
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:
Among the 395 genes, NOTCH3 was identified as a good prognostic factor for GC patients. Its prognostic value was also suggested in both our GC cohort from Zhongshan Hospital and the public databases (KM plotter and GEPIA database). Mechanistically, high NOTCH3 expression correlated with a lower infiltration of activated CD8+ 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.
Insights
NOTCH3 is identified as a prognostic factor in gastric cancer (GC). High NOTCH3 expression correlates with immune tolerance and dampened anti-tumor immunity, suggesting its potential as a therapeutic target.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Gastric cancer (GC) patients often relapse after adjuvant therapy.
- Immune-related mechanisms are crucial in GC, making immunotherapy a promising treatment avenue.
- Investigating immune-related genes can identify new prognostic and therapeutic targets for GC.
Purpose of the Study:
- To investigate the expression and prognostic significance of immune-related genes in gastric cancer.
- To explore the role of NOTCH3 in the tumor immune microenvironment of GC.
- To assess NOTCH3 as a potential predictive marker for immunotherapy in GC.
Main Methods:
- Transcriptome analysis of the tumor immune microenvironment using a 395-gene panel in 48 GC patients.
- Prognostic value assessment and validation using KM plotter, GEPIA, The Cancer Genome Atlas (TCGA), and Tumor IMmune Estimation Resource (TIMER) databases.
- Correlation analysis between NOTCH3 expression, immune cell infiltration, immune checkpoint inhibitors, and immunotherapy biomarkers.
Main Results:
- NOTCH3 was identified as a significant prognostic factor in GC patients.
- High NOTCH3 expression was associated with reduced CD8+ T cell infiltration and increased immunosuppressive cells (Tregs, M2 macrophages).
- NOTCH3 expression correlated with increased immune checkpoint inhibitors and negatively associated with immunotherapy predictive biomarkers (TMB, GEP, IPRES).
Conclusions:
- NOTCH3 plays a role in immune tolerance in gastric cancer.
- NOTCH3 may serve as a potential therapeutic target for overcoming immune evasion in GC.
- NOTCH3 could be a predictive marker for immunotherapy response in gastric cancer patients.
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