T Cell Receptor repertoire analysis reveals antigenic convergence and immunotherapeutic opportunities in Prostate Cancer
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Background
The T-cell receptor β (TCRβ) repertoire reflects antigen-driven adaptive immune responses and provides insight into tumor–immune interaction. In prostate cancer (PCa), the immunosuppressive tumor microenvironment limits effective T-cell activation, and the antigenic drivers shaping intratumoral TCR repertoires remains poorly defined. This study aimed to characterize matched tumor and peripheral TCRβ repertoires from treatment-naïve PCa patients and to identify shared clonotypes and antigenic specificities associated with disease severity.
Methods
Next-generation sequencing was used to profile TCRβ repertoires from matched tumor biopsies and peripheral blood mononuclear cells (PBMCs) obtained from treatment-naïve PCa patients. Repertoires clonality, diversity, and was assessed using established metrics. Antigenic convergence was evaluated using GLIPH2 to identify shared CDR3β motifs and predicted tumor-associated antigen (TAA) recognition. Preliminary functional validation was performed using IFN-γ ELISpot, T-cell expansion, and single-cell RNA sequencing in an independent cohort of PCa patients.
Results
Tumor-derived TCRβ repertoires displayed reduced richness and increased clonality compared with PBCMs, consistent with local antigen-driven expansion. High-grade tumors demonstrated greater interpatient clonotype sharing and motif-level convergence, indicative of recognition of common TAAs. GLIPH2 analysis associated expanded clonotypes with epitopes derived from prostate-specific G-protein coupled receptor (PSGR), prostate-specific membrane antigen (PSMA), and prostate-specific antigen (PSA). Functional validation confirmed that peptide pools containing PSGR-, PSMA-, and Transglutaminase-4 (TGM4)-derived epitopes induced IFN-γ production and antigen-specific T-cell proliferation in vitro. Single-cell RNA sequencing demonstrated an enhanced activation and cytotoxic transcriptional profile in CD3⁺ T cells following stimulation with the peptide pool.
Conclusions
These findings reveal an oligoclonal, antigen-driven intratumoral TCRβ landscape and identify PSGR, PSMA, and TGM4 as immunogenic, potentially actionable targets. Integration of TCR profiling with antigen discovery pipelines may support the development of TCR-based biomarkers and precision immunotherapeutic strategies in prostate cancer.
