Patient-derived tumor organoid platform identifies immunogenic HLA-I peptides for personalized RCC and BC immunotherapy

While cancer immunotherapy has revolutionized treatment, clinical success remains limited, with only a fraction of patients responding. This is largely due to tumor heterogeneity and patient-specific immune profiles, which hinder accurate response prediction. Conventional preclinical models, such as murine systems, often lack the human-specific HLA-TCR complexity, limiting their ability to accurately evaluate immunotherapy responses. There's a critical need for human-based ex vivo models that can precisely mimic the tumor microenvironment and immune cell interactions to predict and personalize immunotherapy strategies.

Researchers established a patient-specific pipeline for precision immunotherapy in renal cell carcinoma (RCC) and bladder cancer (BC). They generated patient-derived tumor organoids (PDTOs) and patient-derived cells (PDCs) from tumor and adjacent healthy tissues. These models underwent immunopeptidome profiling using an in-house microfluidic platform, PeptiCHIP, to identify tumor-associated HLA-I peptides. The immunogenicity of these identified peptides was then assessed by co-culturing them with peptide-expanded, HLA-matched peripheral blood mononuclear cells (PBMCs), followed by functional immune assays to measure CD8+ T cell activation and cytotoxicity.

The established platform successfully identified tumor-associated HLA-I peptides from patient-derived models, demonstrating its capability to pinpoint potential T cell targets. This integrated approach, combining PDCs, immunopeptidomics, and functional immune assays, effectively recreated patient-specific tumor-immune interactions ex vivo. > The study revealed specific peptides capable of inducing antigen-specific CD8+ T cell activation and cytotoxicity directly against the patient's own tumor cells. This functional validation confirms the immunogenicity of the identified peptides, indicating their potential as targets for personalized immunotherapy. The platform enables the discovery of novel therapeutic targets and the evaluation of immune responses in a highly relevant, patient-specific context, bridging a critical gap in translational immunotherapy research.