Tumor-associated MHC class I–peptide complex (pMHC-I)

Tumor-associated MHC class I–peptide complexes (pMHC-I) represent a critical class of therapeutic targets in immuno-oncology, serving as the primary interface between the intracellular proteome of a cancer cell and the adaptive immune system (Blum et al., Annu Rev Immunol, 2013) [1]. These complexes are composed of a polymorphic MHC class I heavy chain (HLA in humans), an invariant β2-microglobulin light chain, and a short peptide (8–11 amino acids) derived from endogenous proteins processed via the ubiquitin-proteasome pathway (Rock et al., Trends Immunol, 2016) [2]. In malignant cells, these complexes present neoantigens from somatic mutations, cancer-testis antigens, or overexpressed self-antigens, which can be recognized by CD8+ T-cell receptors (TCRs) (Schumacher & Schreiber, Science, 2015) [3]. Modern therapeutic modalities, including TCR-engineered T-cells (TCR-T) and soluble TCR-bispecific engagers like Tebentafusp, are designed to exploit these targets to bypass natural immune tolerance and induce potent T-cell mediated cytotoxicity (Nathan et al., N Engl J Med, 2021) [4]. However, the clinical application of pMHC-I targeting is complicated by the necessity for precise HLA-matching (e.g., HLA-A*02:01) and the risk of lethal off-target cross-reactivity with similar peptides in healthy tissues (Linette et al., Blood, 2013) [5]. Additionally, tumors often evade these therapies through the downregulation of MHC expression or mutations in the antigen presentation machinery, necessitating the use of immunopeptidomics and HLA typing as essential biomarkers for patient stratification (Garrido et al., Oncoimmunology, 2016) [6].

Other names

Peptide-MHC complexpMHCpHLATumor-specific MHC-peptide complexHLA-peptide complexMHC-I-restricted antigen

Therapeutic agents target these complexes by utilizing engineered T-cell receptors (TCRs) or TCR-mimetic antibodies to recognize specific peptide-HLA combinations, thereby directing cytotoxic T-cell activity against tumor cells (Nature Reviews Drug Discovery, 2021) [4, 5].