Abstract
Prostate adenocarcinoma (PRAD) is a leading cause of death among men. Messenger ribonucleic acid (mRNA) vaccine presents an attractive approach to achieve satisfactory outcomes; however, tumor antigen screening and vaccination candidates show a bottleneck in this field. We aimed to investigate the tumor antigens for mRNA vaccine development and immune subtypes for choosing appropriate patients for vaccination. We identified eight overexpressed and mutated tumor antigens with poor prognostic value of PRAD, including KLHL17, CPT1B, IQGAP3, LIME1, YJEFN3, KIAA1529, MSH5 and CELSR3. The correlation of those genes with antigen-presenting immune cells were assessed. We further identified three immune subtypes of PRAD (PRAD immune subtype [PIS] 1–3) with distinct clinical, molecular, and cellular characteristics. PIS1 showed better survival and immune cell infiltration, nevertheless, PIS2 and PIS3 showed cold tumor features with poorer prognosis and higher tumor genomic instability. Moreover, these immune subtypes presented distinguished association with immune checkpoints, immunogenic cell death modulators, and prognostic factors of PRAD. Furthermore, immune landscape characterization unraveled the immune heterogeneity among patients with PRAD. To summarize, our study suggests KLHL17, CPT1B, IQGAP3, LIME1, YJEFN3, KIAA1529, MSH5 and CELSR3 are potential antigens for PRAD mRNA vaccine development, and patients in the PIS2 and PIS3 groups are more suitable for vaccination.
Highlights
Prostate adenocarcinoma (PRAD) is the second diagnosed and the fifth death-related malignancy among men worldwide [1]
Cox regression revealed that 13 genes were significantly associated with overall survival (OS) (Fig. 1D) and 70 genes were significantly associated with disease free interval (DFI) (Fig. 1E)
Our results demonstrated that PIS2 and PIS3 had higher telomeric allelic imbalance (HRD-Allelic imbalance (NtAI)), large scale transition (HRD-Large scale transition (LST)) and loss of heterozygosity (HRD-Loss of heterozygosity (LOH)) and combined homologous recombination deficiency (HRD scores) (Fig. 2J, S3F-H)
Summary
Prostate adenocarcinoma (PRAD) is the second diagnosed and the fifth death-related malignancy among men worldwide [1]. Positive responses in patients with PRAD were rarely observed after immunotherapies including programmed cell death protein 1 (PD-1), PD-Ligand 1 (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA4). Sipuleucel-T brought prostate cancer immunotherapy into a sharper focus whereas no significant effect was reported regarding progression-free survival [2, 3]. Novel therapeutics should be developed for effective PRAD treatment. In the past 2 years, under the background of coronavirus disease-2019 pandemic, the enthusiasm for mRNA vaccine development, showing advantages of flexibility, productivity, non-genomic integration, and low immunogenicity [4], was brought into the field of cancer therapy [5]. Previous phase I/II clinical trial showed good tolerability and favorable immune activation of mRNA vaccines CV9103 for PRAD; the subsequent clinical
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