Immunotherapy of BLCA has attracted increasing attention. On the other hand, neoadjuvant therapy has a certain effect on reducing tumor staging to prevent cystectomy(Rey-Cárdenas, Guerrero-Ramos, Lista, Carretero-González, & Velasco, 2021; Yu, Ballas, Skinner, Dorff, & Quinn, 2017). However, research on immune-related markers for BLCA has not well established the clinical prognosis of tumors. Here, we selected BLCA differential genes and prognostic genes upon the threshold of P<0.01. On this basis, four immune-related differential genes were obtained and an immune prognostic model of BLCA was established. Thereafter, TCGA-CCRCC was used as the validation set, and the feasibility of this model in immune-related prognostic model for urinary system tumors was finally determined.
As a member of the OAS family of interferon-induced antiviral enzymes, OAS1 is also an ancient immune-related gene(Hornung, Hartmann, blasser, & Hopfner, 2014). But its prognostic value is rarely studied at present. Previous studies have shown that the high expression of OAS 1 in cancer cells promotes cell viability by mediating the DNA damage mechanism(Kondratova, Cheon, Dong, Holvey〣ates, & Stark, 2020; Padariya et al., 2021). OAS1 is most closely related to neutrophil infiltration in breast cancer (BC), and its high expression predicts poor prognosis of tumor(Zhang & Yu, 2020). As reported by the latest research, OAS1 is involved in the apoptotic process of microRNA-145 in human BLCA cells(Noguchi et al., 2013). This study illustrated the value of OSA1 as an immune-related gene, and its pathogenic mechanism should be further investigated.
As for the APOBEC3 enzyme family, the intrinsic immune defense against viruses is the endogenous source of somatic mutations in numerous human cancers(Constantin, Dubuis, Conde-Rubio, & Widmann, 2021). APOBEC3H (A3H) is the most polymorphic in human APOBEC3 genes, and APOBEC mutation represents the main mutation mode of TCGA-BLCA(Alexandrov et al., 2013; Gu et al., 2016). It has been previously reported that the mutation of APOBEC significantly improves the survival rate of TCGA-BLCA patients as a tumor suppressor gene, and APOBEC-mediated mutations are the possible reasons for the overexpression of FGFR3 mutations in BLCA(Shi et al., 2019). In head and neck cell carcinoma, high APOBEC3H level has an important effect on the immune infiltration and activation of CD8+ T cells(Q. Liu, Luo, Cao, Pan, & Ren, 2020). Therefore, it is reasonable to speculate that the infiltration of A3H in neutrophils may be involved in somatic mutations and affect patient survival.
In the LDLR family, LRP-1 represents the multifunctional scavenger receptor that not only controls different protease and growth factor levels, but also supports the morphology and function of tumor blood vessels(Dedieu & Langlois, 2008; Lillis, Duyn, Murphy-Ullrich, & Strickland, 2008; Theret, Jeanne, Langlois, Hachet, & Dedieu, 2017). It seems to play a decisive role in tumor progression. As a key regulator of the Notch pathway, LRP1 mediates cell growth and differentiation(Grigorenko, Moliaka, Soto, Mello, & Rogaev, 2004). In esophageal squamous cell carcinoma (ESCC), LRP1 affects patient prognosis by inducing the migration and invasion of tumor cells and macrophages(Sakamoto, Koma, Higashino, Kodama, & Yokozaki, 2021). Besides, LRP1 has the strongest correlation with macrophage infiltration in BCLA. It is speculated that macrophages may increase the carcinogenicity of tumor cells through immune infiltration in tumor cells.
AHNAK2 is a key protein for cell migration. Its deletion leads to an increase in p53 reactivity, which affects cancer cell survival and induces the senescence of untransformed cells(Gh Odke, Remisova, Furst, Kilic, & Soutoglou, 2021; Li, Liu, Meng, & Zhu, 2019). AHNAK inhibits the proliferation and metastasis of ovarian cancer and thyroid cancer cells via the Wnt/β-catenin pathway(Bo, Jin, Dai, & Zhou…, 2017; Lin et al., 2021). AHNAK is considered as a new oncogene, whose role and mechanism in cancer need to be further explored. The expression of AHNAK has a certain effect on immune infiltration of lung adenocarcinoma cells(Zheng, Liu, Bian, Liu, & Liu, 2020). Moreover, AHNAK has a certain correlation with six kinds of immune infiltrating cells in BLCA, indicating that it is significant in tumor immunity as a new oncogene and is worthy of further exploration.
In recent years, due to the high accuracy and safety of immunotherapy, immune checkpoint inhibitors (ICIs) have been increasingly applied in clinic, which has become a prominent progress in tumor treatment(Jia et al., 2017; Spigel et al., 2018; Vari et al., 2018). The immune evasion mechanism within tumor microenvironment (TME) of advanced cancer shows high heterogeneity(Jiménez-Morales, Aranda-Uribe, Pérez-Amado, Ramírez-Bello, & Hidalgo-Miranda, 2021; Kim et al., 2021). Apart from programmed cell death protein 1 (PD-1) and its ligand (PD-L1), additional cellular or molecular mechanisms can cause immune dysfunction in TME as well(J. Liu et al., 2021; Scarpitta, Hacker, Büning, Boyer, & Adriouch, 2021). Korpal et al. discovered that the PPARγ/RXRα pathway partially increased the resistance of BLCA to immunotherapy by damaging the infiltration of CD8 + T cells(Korpal et al., 2017). Although anticancer immunotherapy has provided an alternative treatment option for BLCA, there is still a small group of BLCA patients that can benefit from immunotherapy, and the recognized molecular markers for BLCA are still lacking.
Certain limitations should be noted in this study. First, the data were derived from publicly available data. Second, the number of samples decreased after excluding samples with incomplete clinical data or follow-up information. Third, computer language was used in the method. Fourth, due to the different data processing methods, there might be minor deviations from the previous research results. Last, immunotherapy is one of the most concerned areas in cancer treatment today, and there are plenty of studies on immunotherapy. So there may be duplication in the use of data, and the credibility of the results should be further verified.
In summary, the four related genes in this model include the ancient and newly discovered tumor-related genes, which mediate the pathogenesis and progression of different tumors. This study has narrowed the scope of immune genes and increased the screening criteria for the correlation between genes and diseases. In addition, TCGA-CCRCC is used as the model validation set for the sake of verifying our model feasibility and significance in urinary system tumors. It is a supplement and further verification of the previous prognostic models of BLCA, and it is also an important attempt to unify the prognostic models of urinary system tumors.