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

Anqi Lin; Jiarong Yao; Quan Cheng; Zaoqu Liu; Peng Luo; Jian Zhang

doi:10.2147/JIR.S394894

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

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

Authors

Anqi Lin^#¹, Jiarong Yao^#¹, Quan Cheng^{2

3}, Zaoqu Liu⁴, Peng Luo¹, Jian Zhang¹

Affiliations

¹ Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
² Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
³ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
⁴ Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.

^# Contributed equally.

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.

Grants and funding

This work was supported by the Natural Science Foundation of Guangdong Province (Grant No. 2018A030313846 and 2021A1515012593), the Science and Technology Planning Project of Guangdong Province (Grant No. 2019A030317020) and the National Natural Science Foundation of China (Grant No. 81802257, 81871859, 81772457, 82172750 and 82172811).