Identification of Novel Tumor Antigens and the Immune Landscapes of Bladder Cancer Patients for mRNA Vaccine Development

Abstract

BackgroundmRNA vaccines are a novel technology that provide a potential strategy for cancer treatment. However, few studies exist that are focused on the application and development of mRNA vaccines in bladder cancer (BLCA). Therefore, this study filtered candidate antigens and specific mRNA-suitable populations in BLCA via comprehensive multi-omics analysis.MethodsClinical information, follow-up information, and gene expression profiles were obtained from the TCGA and GEO databases. Somatic mutation and DNA copy number variation of BLCA were visualized by cBioPortal. Significant survival genes were analyzed by GEPIA2. TIMER was used to evaluate the connection between candidate antigens and infiltration of antigen-presenting cells. Consensus clustering analysis was performed to identify immune subtypes using the ConsensusClusterPlus package. The Monocle package was used to visualize the immune landscapes of each BLCA patient. Weighted gene co-expression network analysis (WGCNA) was used to identify key genes for mRNA vaccines.ResultsAP2S1, P3H4, and RAC3 were identified as candidate tumor-specific antigens for BLCA. Three immune subtypes were classified based on immune-related gene expression profiles. Patients with the BCS2 subtype were characterized as immune “cold” and exhibited upregulation of immunogenic cell death modulators, whereas patients with BCS1 and BCS3 were immune “hot” and had upregulation of immune checkpoints. Interestingly, patients with the BCS2 subtype had a better prognosis than other subtypes. The immune landscapes of each patient were visualized and revealed the heterogeneity within the BCS1 subtype. Finally, 13 key immune genes were identified.ConclusionsAP2S1, P3H4, and RAC3 were identified as candidate tumor-specific antigens, and patients with the BCS2 and BCS1A subtypes were identified as candidate populations for mRNA vaccines. In summary, this study provides novel insights and a theoretical basis for mRNA vaccine development in BLCA and other malignancies.

Exploitation of tumor antigens and construction of immune subtype classifier for mRNA vaccine development in bladder cancer

“…Gui C et al established a ferroptosis-induced tumor microenvironment landscape in bladder cancer and identified six genes as potent antigens for developing an anti-BLCA mRNA vaccine (52). Wang G et al identified AP2S1, P3H4, and RAC3 as three candidate genes of tumor-specific antigens in bladder cancer using the TCGA BLCA cohort and GSE13507 datasets (53). In contrast to these studies, we integrated four cohorts into a Meta cohort at the outset, including TCGA BLCA, GSE13507, GSE32894, and E-MTAB-4321 cohorts, which enhanced the robustness of our study.…”

“…Wang G et al. identified AP2S1, P3H4, and RAC3 as three candidate genes of tumor-specific antigens in bladder cancer using the TCGA BLCA cohort and GSE13507 datasets ( 53 ). In contrast to these studies, we integrated four cohorts into a Meta cohort at the outset, including TCGA BLCA, GSE13507, GSE32894, and E-MTAB-4321 cohorts, which enhanced the robustness of our study.…”

Integrating single-cell and bulk RNA sequencing to predict prognosis and immunotherapy response in prostate cancer

“…Our analysis results are generally consistent with previous studies. TTN is a commonly mutated gene in cancer and has a prominent role in predicting immune checkpoints and prognosis in solid tumours 57 . TTN mutations have been shown to be an independent risk factor for thyroid cancer and to predict a poorer prognosis for patients 58 .…”

mRNA—From COVID-19 Treatment to Cancer Immunotherapy

“…Bladder cancer AP2S1, P3H4, and RAC3 [174] Melanoma PTPRC, SIGLEC10, CARD11, LILRB1, and ADAMDEC1 [175] Colorectal, NSCLC, and pancreatic cancers KRAS [176] Esophageal squamous cell carcinoma (ESCC) NLRC5, FCRL4, TMEM229B, and LCP2 [177] Soft tissue sarcoma HLTF, ITGA10, PLCG1, and TTC3 [178] Glioblastoma ADAMTSL4, COL6A1, CTSL, CYTH4, EGFLAM, LILRB2, MPZL2, SAA2, and LSP1 [179] Glioma NAT1, FRRS1, GTF2H2C, BRCA2, GRAP, NR5A2, ABCB4, ZNF90, ERCC6L, and ZNF813 [180] Malignant mesothelioma FAM134B, ALDH3A2, SAV1, RORC, and FN1 [181] Stomach adenocarcinoma ADAMTS18, COL10A1, PPEF1, and STRA6 [182] Mesothelioma AUNIP, FANCI, LASP1, PSMD8, and XPO5 [183] Dosing of mRNA can be achieved by titrating up or down, depending on the need, weight, and disease state of the patient. The duration of action is intrinsically limited by mRNA degradation, reducing the likelihood of irreversible side effects, and enabling the treatment of acute indications [184,185].…”