T-cell receptor specific for tumor-associated mitochondrial antigen peptide–MHC complex (MTA-specific TCR)

T-cell receptors (TCRs) specific for tumor-associated mitochondrial antigen (MTA) peptide–MHC complexes are a novel class of therapeutic agents in the field of adoptive cell immunotherapy. These receptors are designed to target peptides derived from the mitochondrial genome (mtDNA) or mitochondrial proteins that are presented on the cell surface by Major Histocompatibility Complex (MHC) molecules (Pierini et al., 2022, Nature Communications). Unlike nuclear-encoded antigens, mitochondrial antigens can arise from somatic mtDNA mutations or metabolic dysregulation, providing a unique pool of neoantigens that may bypass central tolerance (Smith et al., 2021, JCI). By engineering T cells to express these specific TCRs, researchers aim to create highly targeted therapies for solid tumors that are otherwise difficult to treat with conventional CAR-T or TCR-T approaches (Ghorani et al., 2020, Cancer Discovery). The clinical success of this target class depends on the identification of highly specific mitochondrial epitopes to minimize the risk of on-target, off-tumor toxicity in healthy tissues (PubMed, 2023). These TCRs function by forming an immunological synapse upon binding to the pMHC complex, triggering the release of cytotoxic granules like granzymes and perforins. This approach is particularly relevant for cancers with high mutational burdens in the mitochondrial genome, such as certain colorectal and lung cancers. Ongoing research focuses on optimizing TCR affinity and ensuring HLA-restricted presentation to maximize efficacy and safety in diverse patient populations.

Other names

Mitochondrial antigen-specific TCRmtAg-specific TCRMitochondrial-derived peptide-specific TCRmtDNA-encoded antigen-specific TCRMitochondrial neoantigen-specific TCR

Engineered T-cells expressing these TCRs recognize and bind to mitochondrial-derived peptides presented by MHC molecules on tumor cells, leading to T-cell activation and subsequent lysis of the cancer cell.