Coronary artery disease (CAD) is a chronic inflammatory cardiovascular disease caused by structural or functional abnormalities of the coronary arteries, resulting in myocardial ischemia and hypoxia (1). Various clinical manifestations of CAD include myocardial infarction, stable and unstable angina, and sudden cardiac death (2). Although the incidence of coronary heart disease has declined in developed countries recently, it is still one of the main reasons of death with wide variations in the incidence of CAD in developing countries (3, 4). In addition, the incidence, prevalence, and mortality of cancer are increasing, and it is the leading causes of human mortality worldwide (5, 6). The cardiovascular disease shares the same risk factors as cancer, such as smoking, obesity, and diabetes. It has been shown that cardiovascular disease increases the risk of developing cancer, and in some cancer patients, it is the main cause of death (7) and CAD is the most common complication for cancer patients (8). Cardiovascular health (CVH) has recently been identified by the American Heart Association (AHA) as playing a crucial role in the prevention of CAD and cancer (9). However, how CAD and cancer are related is still unknown. Therefore, it is of great research value to find the potential signaling pathways between CAD and cancer and to explore their common therapeutic targets.

CAD is a chronic inflammatory cardiovascular disease that is primarily due to the formation of atherosclerotic plaques within the vessel wall (10). It has been demonstrated that different immune cells and immunological-mediated inflammatory responses play a role in how atherosclerotic plaques develop (11). Among them, INF-γ, IL-17 and IL-21, and B-cell inflammatory genes are significantly increased in people with CAD (12), and IL-17a promotes the epithelial to mesenchymal transition in gastric cancer cells through JAK2/STAT3, exacerbating the development of gastric cancer (13). Immunosuppressive effects of B cells on tumors in the tumor microenvironment (TME) inhibit cancer development (14). In mice studies, B2 lymphocytes were found to produce interferon (IFN) and pathogenic IgG and activate T cells as atherogenic immune cytokines (15). CD8+ T cells are cytotoxic and can kill tumor cells, and T helper 1 (Th1) cells can promote the appreciation of CD8+ T cells and NK cells by secreting IL-2 and IFN-β. The aggregation of these immune cells in TME suggests a good prognosis (16). In CAD development, CD8+ T lymphocytes play two distinct roles. On the one hand, inflammatory cytokines produced by CD8+ T cells boost the inflammatory response and aid in vascular atherosclerosis progression. In contrast, their cytotoxic effect on antigen-presenting cells and the presence of a subpopulation of cells with regulatory effects on CD8+ T cells suppress the immune response and protect against atherosclerosis (17). CAD and cancer share the same immune link, and the development of CAD and cancer is influenced by immune cells and the immunological responses they mediate. Immunotherapy has been used to better effect in the treatment of cancer, and this may be of value in the treatment of coronary heart disease.

Bioinformatics uses mathematics, biology, and computer science to mine. It analyzes data and information from medical and life sciences to explore the underlying mechanisms of disease occurrence via computer software, networks, and other tools (18). GSE60681 dataset associated with CAD from the Gene Expression Omnibus (GEO) database were downloaded to explore the association between immunity in CAD and cancer. Enrichment of the samples was assessed using Gene Set Variance Analysis (GSVA), followed by Weighted Gene Co-Expression Network Analysis (WGCNA) analysis to find the modules most significantly associated with CAD and to identify candidate hub genes. Next, immune-related genes were downloaded from the import database while taking intersections with candidate hub genes from CAD-related modules to identify hub genes. Finally, we assessed its expression levels in normal and different cancer tissues and further performed the hub gene's survival analysis and methylation analysis. In addition, an immune infiltration analysis of CAD and pan-cancer were conducted to explore the correlation among the hub genes, immune cells and cancer. The results may have implications for developing novel immunotherapies for CAD and cancer. Furthermore, the results can open up fresh perspectives on immunotherapies to lower the incidence of CAD in cancer patients.

To date, CAD and cancer are the two major diseases that threaten human health and lead to death. As the world ages, the number of cancer survivors increases, but many cancer treatments and drugs are cardiotoxic. For example, combining bleomycin, bevacizumab, and vincristine can increase the CAD risk by 1.5–7 times (19). Therefore, cancer patients often have coexisting heart disease (20) and are most often seen with CAD in conjunction with cancer (21, 22). On the other hand, immune cells and responses are a crucial link in the onset of cancer and CAD, and immunotherapy has been widely used in treating cancer. Still, the connection between immunity in CAD and cancer has rarely been reported. A recent study has shown that some genes are strongly linked to CD8+ T immune cells responsible for the onset of CAD and cancer (23) and may provide new therapeutic targets for CAD and coronary artery disease. However, the precise mechanisms are not yet known.

In this research, WGCNA was deployed to identify modules significantly associated with CAD in the GSE60681 dataset, and among them, the most immunologically relevant gene, RBP1, was found. RBP1 affects retinoic acid metabolism by reducing retinol transport, is involved in various physiological functions, and plays a crucial part in cancer genesis (24, 25). RBP1 expression levels are highly expressed in CAD and vary in different cancers. RBP1 was strongly expressed in 25 cancers containing ACC, BLCA, BRCA, etc. We paired standard tissue samples from the GTEx database with tumor tissue samples from the TCGA. After that, RBP1 was lowly expressed in 10 tissues, including BLCA, CHOL, ESCA, etc. Kaplan-Meier survival analysis and univariate cox analysis revealed that RBP1's expression level in malignant tumors was linked to poor prognosis. RBP1 silencing is a common epigenetic phenomenon in many human cancers (26). Low or defective RBP1 gene expression is closely associated with developing breast cancer, kidney cancer, prostate cancer, lung cancer, and endometrial cancer (27–29). The prognosis is worse when RBP1 is expressed more frequently. It is closely associated with the malignant biological processes of self-renewal, invasion, and migration in non-glioblastoma diffuse glioma (non-GDG). The NF-κB signaling pathway is related to RBP1-dependent malignancy in non-GDG (30). RBP1 is highly expressed in lung adenocarcinoma and mediates cell proliferation and differentiation by up-regulating Akt/Erk/ EGFR pathway, which is associated with increased tumor grade (31). The expression of RBP1 in tongue squamous carcinoma cells (TSCC) correlates with the degree of tumor differentiation and lymph node metastasis (32), and RBP1 overexpression in oral squamous cell carcinoma (OSCC) promotes the development of cellular autophagy and facilitates the growth and invasion of OSCC (25). Consistent with our results, these studies confirmed the close relationship between RBP1 and cancer and prognosis. According to the findings of our clinical staging, RBP1 expression was higher in the intermediate and late stages of four malignancies, including BLCA and COAD, but was lower in the higher stages of BRCA, ESCA, and MESO tumors. Increased expression of RBP1 may reflect the invasion of cancer. It may be possible to monitor the expression level of RBP1 to evaluate the development of CAD patients with cancer.

The body's immune system regulates tumor occurrence and development. At the same time, macrophages and smooth muscle cells, under the synergistic effect of immune cells and inflammatory factors, phagocytosis of lipids to form foam cells, which promotes the formation of atherosclerosis, which is the mechanism of CAD occurrence and development (33). Interleukin (IL)-1β can reduce the risk of CVD in patients with residual inflammation (34), and methotrexate has anti-inflammatory effects. Although it can treat CVD, it cannot reduce risk and mortality (35). CD4+ T cell-mediated immune responses are involved in the development of CAD (36, 37) and affect the stability of atherosclerotic plaques through the secretion of interferon (INF-γ) in Th1 cells, leading to acute coronary syndrome (ACS) (38, 39). On the other hand, CD8+ T cells are the main cytokine secreting INF-γ. In tumor immunity, INF-γ enhances the inflammatory response associated with Th17 cells promoting tumor development (40), and in the tumor microenvironment, INF-γ inhibits tumor-specific evasion of immune surveillance (41). We analyzed immune cell infiltration in CAD and cancer patients, and the analysis of immune infiltration in CAD showed a significant difference in T cells CD4 naïve in CAD and a significant positive correlation between RBP1 and immune correlation with T cells CD4 naïve. The TIMER study revealed a substantial correlation between RBP1 expression and the immune infiltration of malignancies. CD8+ T cells, CD4+ T cells, cancer-associated fibroblast, etc., were all strongly positively correlated with RBP1 in various tumors. We concluded that RBP1 might be a gene that influences the immune response involved in CAD and cancer development. We also calculated the relation between RBP1 expression levels and immune scores to explore the link between RBP1 and the tumor immune microenvironment. The findings demonstrated that PRAD and UVM tumor immune cell infiltration were positively connected with RBP1, and OV, HNSC, and BRCA tumor immune cell infiltration significantly negatively correlated with RBP1. According to this analysis, RBP1 may impact the tumor's immune microenvironment and the course of cancer.

In addition to immune infiltration, gene mutations are also associated with developing malignant tumors. LGGs with isocitrate dehydrogenase (IDH) gene mutation are more likely to develop into secondary GBMs (42). FOXA1 gene mutation inhibits androgen signaling in prostate cancer and promotes tumor growth (43). We evaluated the mutation types of the RBP1 gene in cancer and showed that RBP1 is the predominant gene in the Amplification mutation type. In addition, according to Kaplan-Meier survival analyses, the set of tumors with RBP1 mutations had a worse prognosis. TMB, MSI, and response to tumor immunotherapy are closely related (44, 45). In BLCA and ACC, RBP1 expression had a negative relationship with TMB but was positively linked with TMB in BRCA, LGG, and LAML tumors. In BRCA, MESO, and DLBC, there was a substantial positive association between RBP1 and MSI, whereas, in STAD, PAAD, and the other five tumors, there was a significant negative correlation. In addition, MMR variants can be used as a predictor of tumors (46), and mutations in the MMR gene constitute a considerable cause of MSI instability in patients with rectal cancer (CRC) (47). In previous studies, MMR deficiency, high TMB, and high MSI were shown to be more effective in immunotherapy (48). The expression levels of RBP1 in PRAD were significantly and positively linked with the levels of mutation of five MMR genes, according to our further analysis of the relationship between RBP1 and MMR gene mutation levels. RBP1 was linked considerably with TMB, MSI, and MMR in various tumors, suggesting that RBP1 could be used as a novel assay in clinical immunotherapy targeting specific populations.

Immunotherapy is one of the main methods to treat cancer. Immunotherapy mainly includes tumor vaccines, checkpoint inhibitors (ICBs), adoptive cell transfer therapy, etc. CAR-T therapy is the most widely used immunotherapy method, and its most common therapeutic targets are extracellular glycoproteins CD19, CD20, and B-cell surface antigens such as BCMA (49). However, there's no appropriate immunotherapy for the medical therapy of CAD. And in some studies of immunotherapy for CAD: the Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) and the Cardiovascular Inflammation Reduction Trial (CIRT), the results showed that optimal immunotherapy for CVD can only be reached by identifying new drug therapeutic targets and blocking specific inflammatory pathways of atherosclerosis (50). Immune checkpoint inhibitors of tumors mainly inhibit programmed cell death protein (PD) 1 and cytotoxic T lymphocyte-associated protein (CTLA) 4 are currently the primary approach to tumor immunotherapy (51). In addition, CTLA4 drives or inhibits plaque inflammation as a critical protein in regulating atherosclerosis. Animal experiments demonstrated that CTLA4 binding to abatacept protein inhibits the interaction between CD28-CD80/CD86 to inhibit atherosclerosis (52). We also looked at the relationship between RBP1 and genes associated with immunological checkpoints. We discovered that RBP1 was positively connected with immune checkpoint activation genes in most cancers, indicating that the amount of RBP1 expression was closely related to immune cell infiltration of tumor cells and immune cell function. Immune checkpoint therapy might be an effective treatment for CAD. Patients with CAD combined with cancer have a hypercoagulable state of blood and coagulation disorders due to the tumor itself, which can exacerbate the progression of the disease (53). In addition, since drugs for cancer treatment are often accompanied by cardiac toxicity, fatal fulminant myocarditis caused by immune checkpoint inhibitors has also been reported in the literature, even if the mechanism of immune checkpoint inhibitors is different from that of previous chemotherapy (54). Considering that RBP1 may be a potential gene related to CAD and cancer, we examined how RBP1 and anticancer drug sensitivity are related using the CallMiner database. The outcomes demonstrated a positive connection between the IC50 of E-7820 and the expression of RBP1. However, it was negatively correlated with the IC50 of Vemurafenib, Epothilone B, Dabrafenib, XL−147, and Raloxifene. This result further expands the clinical value of RBP1.

The mechanism and function of RBP1 are further explored. Analysis of enrichment showed that RBP1 was significantly enriched in biological processes such as mitochondrial protein-containing complex mitochondrial, proteasome complex, respiratory chain complex I, and cell mitotic cycle. The mitochondria play an essential role in cancer development; mitochondrial ubiquinol oxidation in tumor cells is required for cancer proliferation (55). Pten-induced kinase 1 (PINK1)/ Parkin-mediated mitochondrial autophagy drives the proliferation of vascular smooth muscle cells (VSMCs), which in turn leads to atherosclerotic lesions and the development of CAD (56). Therefore, CAD and cancer development may be associated with impairing mitochondrial function. GSEA analysis showed that RBP1 was mainly enriched in the activation of the immunological response, regulation of cell surface receptor signaling pathways, graft immune rejection, and Epithelial-mesenchymal transition (EMT) pathways. These pathways correlate with the type of immune response in different cancers. Analysis of RBP1 and cancer-related functional states showed that it was negatively correlated with 12 cancer-functional conditions in UM tumors and significantly positively correlated with seven cancer-functional states in lung adenocarcinoma (LUAD), including angiogenesis, quiescence, and inflammation. Angiogenesis is essential for the tumorigenesis, growth, metastasis, and dissemination of tumors (57). It has been shown that angiogenic genes can be used as biomarkers for immune infiltration and cancer development associated with LUAD in clinical settings (58). Therefore, RBP1 may be able to be a marker for LUAD treatment as well as for assessing prognosis. In addition, DNA methylation is the most critical form of epigenetic modification (59). Analysis of the disease myth 3.0 database showed that RBP1 was hypermethylated in CAD and 11 tumors, including PAAD, COAD, and LUAD. Epigenetic disruption of RBP1 is a common occurrence in human cancers. In particular, the highest frequency of RBP1 hypermethylation was observed in lymphomas and gastrointestinal tumors (60), and the expression of the RBP1 gene is very closely related to its promoter methylation (61). The connection between four DNA methyltransferases and RBP1 are examined. RBP1 was associated with at least one DNA methyltransferase in multiple tumors. These results suggest that aberrant expression of RBP1 can mediate CAD and cancer development through the regulation of DNA methylation.

In summary, RBP1 has been identified bioinformatically as a potential essential gene that may connect CAD and cancer by way of an immune response. In a pan-cancer analysis, RBP1 was strongly associated with immune infiltration and prognosis in different cancers and may become a new therapeutic target. In the future, developing targeted or novel immunotherapies against RBP1 may reduce the incidence of CAD in cancer patients. However, this study was based on bioinformatics analysis, and there have not been any reported studies related to RBP1 and CAD, more research needs to be done in follow-up experiments to identify the specific mechanisms of RBP1 development in CAD and cancer.