T cell receptor recognizing mutant Von Hippel-Lindau peptide-MHC complex (TCR-mutVHL) (TCR-mutVHL)

The T cell receptor (TCR) recognizing mutant Von Hippel-Lindau (VHL) peptide-MHC complexes is a specialized immune protein designed to identify neoantigens produced by mutations in the VHL tumor suppressor gene. These mutations, particularly frame-shifts like the c.452delG (p.Gly151fs) mutation, are characteristic of over 80% of clear cell renal cell carcinoma (ccRCC) cases and result in the production of novel peptide sequences that are absent in normal tissues (Gossage et al., 2015, Nature Reviews Cancer). The TCR is engineered to bind these specific mutant peptides when they are presented on the cell surface by Major Histocompatibility Complex (MHC) molecules, most commonly HLA-A*02:01 (Yang et al., 2022, Journal of Clinical Investigation). Once the TCR engages the peptide-MHC complex, it initiates a signaling cascade that activates CD8+ cytotoxic T lymphocytes to destroy the cancerous cell through the secretion of cytotoxic granules like perforin and granzyme. This targeting strategy is primarily utilized in TCR-engineered T-cell (TCR-T) therapies, providing a highly specific mechanism to treat solid tumors that are otherwise resistant to conventional immunotherapies. Research in this area focuses on identifying high-affinity TCR sequences that can effectively distinguish between mutant and wild-type VHL to ensure safety and efficacy while avoiding off-target effects.

Other names

VHL-specific T-cell receptorMutant VHL-targeting TCRVHL neoantigen-specific TCRTCR-VHL-MHC complex

The TCR specifically recognizes and binds to mutant VHL-derived neoantigen peptides presented by MHC Class I molecules (e.g., HLA-A*02:01) on tumor cells, triggering T-cell activation and targeted lysis of the malignant cells.