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. 2023 Apr 17:16:1693-1709.
doi: 10.2147/JIR.S394894. eCollection 2023.

Mutations Status of NOTCH Signaling Pathway Predict Prognosis of Immune Checkpoint Inhibitors in Colorectal Cancer

Anqi Lin #  1 , Jiarong Yao #  1 , Quan Cheng  2   3 , Zaoqu Liu  4 , Peng Luo  1 , Jian Zhang  1
Affiliations

Mutations Status of NOTCH Signaling Pathway Predict Prognosis of Immune Checkpoint Inhibitors in Colorectal Cancer

Anqi Lin et al. J Inflamm Res. .

Abstract

Purpose: In recent years, tumour immunotherapy has ushered in a new era of oncology treatment. However, the use of immune checkpoint inhibitors (ICIs) in the treatment of CRC remains limited. There is an urgent clinical need for precise biomarkers that can aid in the screening and treatment of CRC subtypes. Therefore, we focused on the NOTCH pathway mutation status and conducted a systematic analysis for its predictive value of ICI therapy efficacy.

Methods: We collected mutational and clinical data from cohorts of CRC patients treated with ICIs. The relationship between NOTCH pathway mutations (NOTCH-MT) and CRC immunotherapy prognosis was analysed using univariate and multivariate Cox regression models. CRC cohort data from The Cancer Genome Atlas (TCGA) database were combined to obtain a comprehensive overview of immunogenicity and tumour microenvironment (TME) differences among different NOTCH pathway mutation statuses.

Results: We observed greater infiltration of M1 macrophages, CD8+ T cells, neutrophils, and activated natural killer (NK) cells with NOTCH-MT status. Immunogenicity was also significantly higher in patients with NOTCH-MT, as were tumour mutational burden (TMB), neoantigen load (NAL), and the number of mutations in DNA damage repair (DDR) pathways.

Conclusion: NOTCH-MT status was strongly associated with the prognosis of CRC patients treated with ICIs and is expected to serve as a novel biomarker and therapeutic target for CRC.

Keywords: CRC; ICIs; NOTCH; biomarker; tumour microenvironment.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The predictive value of clinical characteristics and NOTCH signalling pathway mutation status for ICI efficacy. (A) Data processing flowchart of the study. (B) Kaplan-Meier (KM) survival curves for overall survival rate (OS) in 109 ICI-treated CRC patients. (C) KM survival curves for OS in the TCGA-CRC cohort.
Figure 2
Figure 2
(A) Genomic profiles of patients with colorectal cancer treated with ICIs.The top 20 genes with the highest mutation frequencies and the corresponding clinical information are shown in the figure. (B) Heatmap depicting the mutual exclusion co-occurrence analysis results for the top twenty mutated genes (*p<0.05; **p<0.01; and ****p<0.0001; Mann–Whitney U-test).
Figure 3
Figure 3
NOTCH-MT CRC was associated with increased tumour immunogenicity. The TMB of NOTCH-MT and NOTCH-WT tumours from the ICI-treated CRC cohort (A), the local CRC cohort (B), and the TCGA-CRC cohort (C) were compared. (D) Comparison of NAL NOTCH-MT and NOTCH-WT tumours from the TCGA-CRC cohort. (E) Comparison of DDR signalling alterations between the NOTCH-MT and NOTCH-WT groups in the TCGA-CRC cohort (*p<0.05; **p<0.01; ***p<0.001; and ****p<0.0001).
Figure 4
Figure 4
NOTCH-MT CRC was associated with significant immune cell enrichment and improvement in immune scores. Comparison of the proportions of immune cells using the CIBERSORT method (A), EPIC (B), and IPS (C) NOTCH-MT and NOTCH-WT tumors in the TCGA-CRC cohort for immune-related scores between NOTCH-MT and NOTCH-WT tumors in the TCGA-CRC cohort. The immune-related scores were Th1 Cell (D), Th2 Cell (E), Macrophage Regulation (F), and Lymphocyte Infiltration Signature (G) (*p<0.05; **p<0.01; ***p<0.001; and ****p<0.0001).
Figure 5
Figure 5
(A) Comparison of immune checkpoint gene expression in the TCGA-CRC cohort.(B) The immune-related gene heatmap depicts the relative expression of 30 immune-related genes (antigen presentation/CD4+ regulatory T-cell/CD8+ T-cell/cytolytic activity/NK cell/stimulation/inhibition) in patients with NOTCH-WT and NOTCH-MT CRC from the of TCGA-CRC cohort. NOTCH-MT and NOTCH-WT tumours in the TCGA-CRC cohort exhibit differentially enriched biological functions (identified by GSEA). In the TCGA-CRC cohort, differences in classical immune-related pathways (C) and exhaustion-related factors (D) were observed between NOTCH-WT and NOTCH-MT CRC patients (identified by GSEA)(*p<0.05; **p<0.01; ***p<0.001; and ****p<0.0001).
Figure 6
Figure 6
(A) In the TCGA-CRC cohort, differences in immune cells (A) and cytokines (B) were observed between NOTCH-WT and NOTCH-MT CRC patients (identified by GSEA).
Figure 7
Figure 7
Comparison of NOTCH-MT and NOTCH-WT tumours in the TCGA-CRC cohort using ssGSEA (**p<0.01; ***p<0.001; and ****p<0.0001).
Figure 8
Figure 8
Potential mechanism underlying the prognostic value of NOTCH-MT.
See this image and copyright information in PMC

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