STAD is common cancer and remains the leading cause of cancer-related deaths in the worldwide[2]. In recent years, the OS of STAD patients has been improved to a certain extent with development of therapy and medicine, but there is still space for improvement. As well known, it is of great significance for improving the clinical prognosis of patients that well understanding the mechanism of the occurrence and development of cancer. Immunological mechanisms regulate the progression of STAD, and many different immunotherapies have been proposed as a means of effectively treating methods[7]. TGFBR1 act as important roles in the TGF‑β family, and have important effects on cell reproductive capacity, growth and immunological reactions[19].
In this report, we assessed the expression of TGFBR1 as it related to the prognosis of 33 different types of cancers using the TIMER2.0 databases, revealing obvious differences between tumor and normal tissue expression of TGFBR1 in many cancers. TCGA data set analysis indicated that there was elevated TGFBR1 expression in CHOL, COAD, GBM, HNSC, LIHC, PCPG, STAD and THCA, whereas expression was decreased in BLCA, BRCA, KIRP, KIRC, LUAD, LUSC, PRAD and UCEC relative to adjacent controls. Altered TGFBR1 expression in a range of different cancers may relate to differences in the underlying biological mechanisms. Particularly, elevated expression of TGFBR1 also was observed in STAD through GEPIA. We confirmed the prognostic value of a signature built with 20 TGFBR1-related genes (Figure 3 and Table S2). The risk score of the TGFBR1-related signature was a stable, independent prognosis factor in TCGA datasets. Furthermore, elevated TGFBR1 correlated with poorer patient prognosis, as well as, stage, T stage, N stage, and differentiation. Elevated TGFBR1 expression in STAD correlated with a higher stage, N stage, T stage, and poor differentiation. This elevated TGFBR1 expression was also a reliable predictor of the presence of lymph node metastasis in STAD patients, indicating that TGFBR1 may be a valuable prognostic indicator of metastatic progression in STAD. These results together thus suggest that TGFBR1 may have value as a STAD prognostic biomarker and associated with progression of STAD.
In this study, we found that TGFBR1 expression correlated with patient prognosis in STAD, with a particularly strong correlation between high TGFBR1 expression and a poor STAD prognosis. Across these databases, we consistently observed a correlation between elevated TGFBR1 expression and a poor STAD prognosis. In the TCGA database, elevated TGFBR1 levels were correlated with a poorer outcome for patients with STAD. Similarly, the Kaplan-Meier plotter database found elevated TGFBR1 to correlate with poor GC outcome. What’s more important, ROC analysis also confirmed the diagnostic value. In recent years, there was no predictive nomogram for STAD combining the TGFBR1 expression reported. Therefore, a prognostic nomogram involving T, M, N classification, age, pathologic stage, primary therapy outcome, histologic grade and TGFBR1 was constructed, which can be used by the physician to improve the accuracy of identifying high risk STAD patients. Multivariate Cox analysis further confirmed that high TGFBR1 expression was an independent risk factor for OS in STAD patient. Moreover, high TGFBR1 expression was correlated with clinicopathologic features in STAD, including primary therapy outcome, histologic grade and age. The result showed that high TGFBR1 expression was correlated with advanced gastric cancer, which indicated that it may be a marker to identify early STAD and advanced STAD. We conclude that the poor survival in STAD has a probable prognostic molecular marker known as the TGFBR1 expression. Also, possible key pathways in STAD that is regulated by TGFBR1 are the focal adhesion, pathway in cancer, NOTCH signaling pathway, MAPK signaling pathway, chemokine binding, and positive regulation of VEGF-C production. Finally, the results further suggest that for improved clinical outcomes among STAD patients, we could use an independent prognostic factor known as the high TGFBR1 mRNA expression. We recommend further research on the subject matter to progressively improve the evidence on the biological impact of TGFBR1.
A key finding in this study is that the TGFBR1expression correlated with the degree of immune infiltration level in STAD. We found that TGFBR1 expression was positively correlated with the degree of CD4+ T cells, CD8+ T cells, Macrophages, Neutrophils and Myeloid dendritic cells infiltration in STAD. The results showed that the patient with higher TGFBR1 expression and lower CD8+ T cells infiltration level could be had poor prognosis. We further observed that macrophage infiltration to be significantly associated with prognosis in STAD (Figure 7B). In high TGFBR1 expression group, the patient with higher Macrophage infiltration level could be have poor prognosis. We observed a correlation between TGFBR1 and M1/M2 macrophage markers including PTGS2, CD163, VSIG4 and MS4A4A (Table 4). This suggests that TGFBR1 play an important role in regulating TAM polarization. Also, we found TGFBR1 levels in STAD was related to markers of Treg cells and T cell exhaustion (CCR8, FOXP3, STAT5B, TGFB, HAVCR2, PDCD1 (Table 4). This suggests that TGFBR1 could participated in regulating Treg responses to suppress T cell-mediated immunity. Besides, we observed a correlation between TGFBR1 and NK cell markers including KIR2DL1, KIR2DS4, KIR3DL1, KIR3DL2 (Table 4). NK cells respond rapidly to tumor cells and virus-infected cells through the unique capacity to recognize stressed cells in the absence of an adaptive response, allowing a rapid immune reaction[6]. The result may reveal that TGFBR1may participate in regulating NK cell-mediated rapid immune reaction or innate immunity. What’s more, we observed that TGFBR1 expression correlated with multiple T cell markers (Th1, Th2, Tfh and Th17). This may correspond to the ability of TGFBR1 to regulate T cell responses in STAD. Together, the correlation observed between TGFBR1 and certain immunological marker genes demonstrated that TGFBR1 could regulate immune cell infiltration and interactions within the tumor microenvironment in STAD.
In addition, the TGFBR1 expression level is positively correlated with the expression levels of CD86, CD276, PDCD1LG2, C10orf54, CTLA4, CD28 and NCR3LG1 in STAD. The correlation observed between TGFBR1 and the expression of 15 Immune checkpoint (B7 and CD28 family) suggests that TGFBR1 participated in regulating immune cell infiltration and interactions within the tumor microenvironment in STAD tumors. Together, these results highlight the ability of TGFBR1 to take part in potentially regulating immune cell recruitment and activation in STAD. The TGFBR1 expression correlated with the expression of several immune checkpoint, highlighting a possible role for TGFBR1 in the immunological interaction in STAD, making it a valuable biomarker worthy of further research in this type of cancer.