As a malignant tumor with a morbidity of second and a mortality rate of third, there are about 1.8 million new cases of colorectal cancer in 2018 and caused about 550000 deaths (1). Therefore, the research on colorectal cancer needs further study. Studies have shown that the immune system greatly influences the occurrence and development of tumors, immunotherapy for tumors is also more and more put into clinical application and achieved good results (15–17). However, as the largest histological type of colorectal cancer, the specific immune research on colorectal adenocarcinoma is still scarce, so the influence of immune genes and immune cells on colorectal adenocarcinoma has high research value. In this study, we developed a four-gene prognostic risk model for colorectal adenocarcinoma that can be used as an independent risk predictor of patient survival. Compared with age, gender and pathological stage, this model has higher prediction accuracy. Immune cell infiltration analysis also showed that two kinds of immune cells related to survival were correlated with the model, which suggested that this model could affect the patients' prognosis through immune infiltration.
In the analysis of differentially expressed genes between normal tissues and adenocarcinoma tissues, 497 immune genes were obtained. Enrichment analysis of BP and KEGG pathways showed that these genes affected immune response, signal transduction and other biological processes, as well as cytokine-cytokine receptor interaction, chemokine signaling pathway and other pathways. These provide some reference for further basic experiments. Among them, 36 immune genes were associated with survival. Finally, four ideal immune genes (THRB, IL1RL2, LGR6 and LTB4R2) were included in the risk model. The protein encoded by THRB is one of the receptors of thyroid hormone, which mediates the biological activity of thyroid hormone (18). Studies have shown that the expression of THRB in the nucleus represents the poor prognosis of breast carcinoma patients (19). IL1RL2 was expressed in intestinal T lymphocytes, which induced the proliferation of CD4 + lymphocytes, and low expressed in colon of patients with Hirschsprung’s disease, resulting in increased inflammation and changes in mucosal healing (20, 21). LGR6 encodes a glycoprotein hormone receptor, which is highly expressed in colon carcinoma and has tumor promoting effect. It can be used as an independent risk factor and a biomarker for the diagnosis and prognosis of colon carcinoma (22, 23). LTB4R2, a member of the G protein-coupled receptor (GPCR) family, greatly influences the progresses of many diseases including tumor and asthma (24, 25). Research has shown that LTB4R2 promoted the invasion and metastasis of bladder carcinoma through a reactive oxygen species-linked pathway (26).
To estimate the risk predictive capacity of the model, we used the univariate COX analysis to calculate the correlations among clinical variables, Risk Score and survival. The results showed that pathological stage and Risk Score could be regarded as independent risk predictors. Further multivariate Cox analysis showed compared to other clinical variables, the Risk Score had more satisfying predictive ability. Besides, the genes in this risk model were also correlated with clinical parameters. With the increase of age, the expression of IL1RL2 increased. Meanwhile, THRB was positively correlated with N stage and pathological stage. LGR6 showed the same relationship with age, M stage and pathological stage.
Immune cells infiltration is an important part of tumor immunity, which affects the treatment and prognosis of various cancers (27–29). In this study, we found that the Risk Score of the model was correlated with four kinds of immune cells, in which Macrophages M0 was positively correlated, while Macrophages M1, T cells follicular helper and NK cells activated were negatively correlated. Survival analysis showed that the high expression of Macrophages M0 represents the poor prognosis of the patients, while the higher level of T cells follicular helper represents a longer survival. Qun Zhang et al. reported that in ovarian cancer, the apoptosis of tumor cells stimulated the differentiation of Macrophages M0 to M2, and promoted the proliferation and migration of tumor, which provided a possible chemotherapy scheme for patients with ovarian cancer (30). In addition, higher T cells follicular helper represent a better prognosis in patients with colon and breast cancer (31–33). In this study, high Risk Score represent higher Macrophages M0 and lower T cells follicular helper levels, which have adverse effects on the survival of patients. However, the model derived from this analysis needs to be further verified by clinical samples and basic experiments to obtain the exact impact of the model on the prognosis of patients with colorectal adenocarcinoma.