HLA-A*02-restricted tumor-antigen-specific T cell receptor (HLA-A2-restricted TCR)

The HLA-A*02-restricted tumor-antigen-specific T cell receptor (TCR) is a recombinant or naturally derived heterodimeric protein designed to recognize specific intracellular tumor antigens presented by the Human Leukocyte Antigen (HLA)-A*02:01 molecule [1]. Unlike Chimeric Antigen Receptors (CARs), which are limited to surface proteins, these TCRs can detect peptides derived from the entire cellular proteome, including intracellular oncogenic drivers and cancer-testis antigens [2]. This recognition is highly specific to the HLA-A*02 allele, which is the most common MHC class I allele in Caucasian populations, making it a high-priority platform for precision oncology [3]. Upon binding to the peptide-MHC complex, the TCR initiates a signaling cascade through the CD3 complex, leading to T-cell activation, cytokine production, and the targeted lysis of tumor cells [1, 4]. Therapeutically, these receptors are utilized in TCR-engineered T-cell (TCR-T) therapies and soluble TCR-bispecific molecules (ImmTACs) [2]. Notable examples include Afamitresgene autoleucel, which targets MAGE-A4 for synovial sarcoma, and Tebentafusp, which targets gp100 for uveal melanoma [1, 5]. The primary clinical challenges include off-target cross-reactivity, where the TCR recognizes similar peptide sequences in healthy tissues, and on-target off-tumor toxicity if the antigen is expressed at low levels in normal cells [4, 6]. Consequently, patient eligibility is strictly determined by HLA-A*02:01 genotyping and confirmed expression of the target antigen within the tumor [1, 5].

Other names

T cell receptor recognizing HLA-A2–restricted tumor-associated antigen peptidesHLA-A*02-restricted TCRMHC-restricted T-cell receptorTumor-specific TCRAntigen-specific TCR

The TCR binds specifically to a peptide-HLA-A*02 complex on the tumor cell surface, triggering the CD3 signaling complex to activate T-cell effector functions, including the release of perforin and granzymes and the secretion of pro-inflammatory cytokines like IFN-gamma, resulting in tumor cell apoptosis [1, 4].