Genetic prognostic markers are essential to the diagnosis and prognosis of cancers, and identifying more prognostic markers can improve our understanding of WT. Although the diagnosis and prognosis of WT have been dramatically improved by standardized surgical treatments such as early diagnosis and preoperative chemotherapy, chemotherapeutic drug resistance and immune tolerance still pose a major challenge.  Therefore, further exploration of the mechanism of WT is warranted. The pan-cancer analysis results show that TICAM1 is either highly or lowly expressed in other cancers, but in the WT TARGET cohort and external validation cohort GSE66405, it is confirmed that TICAM1 expression in WT tissue is significantly lower than that in normal tissue (p < 0.05). Although TICAM1 has been extensively studied in inflammation responses and some cancers such as prostate cancer , breast cancer , and colorectal cancer , there is still a lack of knowledge about the role of TICAM1 in WT progression. The effect of immune microenvironment of WT has not been clarified yet, but our study suggests that TICAM1 affects immune cell distribution in WT tissue. In the present study, the influence of TICAM1 on WT is explored for the first time.
TICAM1, also known as a TIR domain-containing adapter inducing IFN-β (TRIF) protein, is a coding protein and an innate immune system protein . Increasing evidence demonstrates that TICAM1 participates in TLR3-TICAM1, TLR4-TICAM1 signaling pathways and type I IFN induction. TLR3-TICAM1 and TLR4-TICAM1 pathways and type I IFNs are important inflammation response pathways that mediate specific immune responses to malignant cells . Moreover, TLR3-TICAM1 pathway promotes the development of important immune cells to resist tumor, such as dendritic cells and macrophages. TICAM1 has been found to participate in immune responses and promote apoptosis in other cancers . The role of TICAM1 in tumors is tissue-specific and its expression varies in different tumors. TICAM1 may up-regulate and down-regulate the expression of different genes via the same pathway in different tumors, thus forming diversified gene expression profiles and playing divergent roles in tumor development and evolution. Previous studies proved that activating TLR3/TICAM1 signaling could suppress multiple myeloma progression . Based on the above findings, the role TICAM1 in WT progression, metastasis and relapse requires further research.
In this study, the group with low TICAM1 expression has worse overall survival and a more advanced clinical stage. It indicates that TICAM1 acts as a suppressor of WT and has a predictive value. This finding is consistent with that of the previous study, which concluded that activating TLR3/TICAM1 signaling could arrest the progression of multiple myeloma. The GSEA functional enrichment analysis results reveal that inflammation responses, apoptosis, NFKB-mediated TNFA signaling and coagulation are significantly more intense in the group with high expression of TICAM1. It implies that a low expression level of TICAM1 in WT can promote WT progression. The enriched apoptosis in the high expression group and inhibited apoptosis in the low expression group suggests that curbing apoptosis encourages WT progression. TLR3-TICAM1 signaling is an inflammation response pathway, and in WT, downregulated TICAM1 may prevent inflammation responses to tumor cells. TICAM1 can also enhance anticancer immunity by stimulating NFKB generation, and low TICAM1 expression in WT may weaken anticancer immunity and accelerate the progression of WT cells [19, 20]. TICAM1 not only participates in inflammation responses but also affects the immune system. Immune cells and cytokines facilitate the occurrence, progression, metastasis, and relapse of cancers, so an immune infiltration algorithm is used to evaluate the association of TICAM1 with immune infiltration and the distribution of immune cells. The ESTIMATE algorithm analysis results show that lower expression of TICAM1 leads to lower immunity. Two groups with different TICAM1 expression levels have different immune conditions, and the low expression group presents higher immune resistance. According to the CIBERSORT algorithm analysis results, the expression of TICAM1 mRNA is negatively related to M2 macrophages. That is to say, a lower expression level of TICAM1 results in more M2 macrophages. Researchers have established that elevated M2 macrophages suggests enhanced immunosuppressive functions, so it will further lead to lower expression of TICAM1 and poorer prognosis in WT patients . As indicated by the MCPcounter algorithm results, T cells, monocytic lineage cells, myeloid dendritic cells and fibroblasts are decreased in the low expression group. The decline of these cells will intensify immunosuppressive activities. T cells are vital to antitumor immunity, and TICAM1 boosts the production and maturation of dendritic cells, which are important immune cells . TLR3, which is positively correlated to TICAM1, is also downregulated in WT tissue. TLR3-TICAM1 participates in induction of myeloid dendritic cells and antitumor macrophages . However, low expression of the TLR3-TICAM1 pathway reduces the dendritic cells and increases M2 macrophages, thereby weakening immune responses to tumor cells and stimulating tumor cells to progress. Immunosuppression is associated with rapid tumor progression, chemotherapeutical drug resistance and tumor metastasis . The number of type I IFNs produced is decreased in WT patients with a low expression level of TICAM1. Nevertheless, type I IFNs play an essential role in specific immune responses to malignant cells, such as tumor cells. Therefore, TICAM1 has great significance in initiating immune and inflammatory responses.
The importance of TICAM1 is comprehensively illustrated in this study, but it also has some limitations. First, this study is based on bioinformatics analyses, and the data are originated from public databases, so it lacks the verification of experiment data. Second, the immunity is assessed by algorithms, and the immunity of WT patients in clinical practice should be examined by experimental observation. Further in-depth studies are required to address the relationship between the expression level of TICAM1 and immune infiltration.
In conclusion, TICAM1 is downregulated in WT, which is significantly associated with a poor survival prognosis and a more advance clinical stage. Downregulated TICAM1 may be involved in tumor associated immune responses and tumor progression. Besides, according to basic pathway mechanisms and bioinformatics prediction results, downregulated TICAM1 is likely to promote the generation of M2 macrophages and weaken immune responses to tumor cells. Therefore, TICAM1 is a potential therapeutic target in WT.