Abstract
In recent years, tumor immunotherapy has become an important treatment program and popular research focus. However, the use of immune checkpoint inhibitors (ICI) in the treatment of colorectal cancer still has limitations due to the current markers only being able to predict the prognosis of a small number of patients. As the chemokine signaling pathway can promote the anti-tumor response of the immune system by recruiting immune cells, we explored the relationship between mutations in the chemokine signaling pathway and the prognosis of colon adenocarcinoma (COAD) patients receiving ICI treatment. To analyze the relationship between chemokine mutation status and the prognosis of patients receiving ICI treatment, clinical and mutation data, with immunotherapy, for a COAD cohort was obtained from “cbioportal.” Then, combining this with COAD cohort data from The Cancer Genome Atlas (TCGA) database, the panorama of gene mutation, immunogenicity, and difference in tumor microenvironment (TME) of chemokine pathways with different mutation statuses were analyzed. High-mut status has been proved to be a prognostic indicator of COAD patients receiving ICI treatment by Univariate and Multivariate Cox regression analysis. CIBERSORT analysis showed that the infiltration degree of M1 macrophages, neutrophils, and activated natural killer (NK) cells was higher in those with high-mut status. Immunogenicity of the high-mut group was also significantly increased, with the mutation number of tumor mutation burden (TMB), neoantigen load (NAL), DNA damage repair (DDR) pathway and microsatellite instability biomarker (MSI-H) being significantly higher. In this study, we found that the mutation state of chemokine pathways is closely associated with the prognosis of COAD patients undergoing ICI treatment. The higher number of TMB, NAL, and DDR mutations and inflammatory TME, may be the mechanism of behind a better prognosis. This discovery provides a possible idea for ICI therapy of COAD.
Highlights
Colorectal cancer is a malignant tumor of the gastrointestinal tract, which originates in the colon or rectum
We found that the number of non-synonymous mutations in the DNA damage repair (DDR) pathway in patients with high-mut was significantly higher than that in patients with low-mut, in both the immune checkpoint inhibitors (ICI)-treated, and TCGACOAD cohorts (p < 0.05; Figures 4A,B)
We found that the expression of immune checkpoint molecules, which are an important means for tumors to escape immune surveillance and an important marker to predict the prognosis of immunotherapy (Darvin et al, 2018), was higher in high-mut patients
Summary
Colorectal cancer is a malignant tumor of the gastrointestinal tract, which originates in the colon or rectum. Mismatch repair deficient (dMMR)/microsatellite instability high (MSIH) is the preferred biomarker for ICI treatment of COAD, and the effect of treatment with ICIs on these patients is remarkable. For patients with mismatch repair proficient (pMMR), microsatellite stable (MSS) or microsatellite instability low (MSI-L) status, it is unable to effectively predict the efficacy of ICI treatment (Ganesh et al, 2019). The research on TMB is only based on dMMR and MSI-H patients (Schrock et al, 2019; Loupakis et al, 2020), and there is no difference in immune spectrum between tumor cells and tumorinfiltrating lymphocytes (TILs) between POLE-MT and POLEWT (Ahn et al, 2016).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
