Dissection of tumor antigens and immune landscape in clear cell renal cell carcinoma: Preconditions for development and precision medicine of mRNA vaccine.

Abstract

Accumulating evidence reveals that mRNA-type cancer vaccines could be exploited as cancer immunotherapies in various solid tumors. However, the use of mRNA-type cancer vaccines in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to identify potential tumor antigens for the development of an anti-ccRCC mRNA vaccine. In addition, this study aimed to determine immune subtypes of ccRCC to guide the selection of patients to receive the vaccine. Raw sequencing and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Further, the cBioPortal website was used to visualize and compare genetic alterations. GEPIA2 was employed to evaluate the prognostic value of preliminary tumor antigens. Moreover, the TIMER web server was used to evaluate correlations between the expression of specific antigens and the abundance of infiltrated antigen-presenting cells (APCs). Single-cell RNA sequencing data of ccRCC was used to explore the expression of potential tumor antigens at single-cell resolution. The immune subtypes of patients were analyzed by the consensus clustering algorithm. Furthermore, the clinical and molecular discrepancies were further explored for a deep understanding of the immune subtypes. Weighted gene co-expression network analysis (WGCNA) was used to cluster the genes according to the immune subtypes. Finally, the sensitivity of drugs commonly used in ccRCC with diverse immune subtypes was investigated. The results revealed that the tumor antigen, LRP2, was associated with a good prognosis and enhanced the infiltration of APCs. ccRCC could be divided into two immune subtypes (IS1 and IS2) with distinct clinical and molecular characteristics. The IS1 group showed a poorer overall survival with an immune-suppressive phenotype than the IS2 group. Additionally, a large spectrum of differences in the expression of immune checkpoints and immunogenic cell death modulators were observed between the two subtypes. Lastly, the genes correlated with the immune subtypes were involved in multiple immune-related processes. Therefore, LRP2 is a potential tumor antigen that could be used to develop an mRNA-type cancer vaccine in ccRCC. Furthermore, patients in the IS2 group were more suitable for vaccination than those in the IS1 group.