Tumor-specific neoantigen–MHC complex (pMHC)

Tumor-specific neoantigen–MHC complexes are molecular assemblies consisting of a mutated peptide fragment (neoantigen) derived from a non-synonymous somatic mutation and a Major Histocompatibility Complex (MHC) molecule [1, 2]. These complexes are presented on the surface of tumor cells and antigen-presenting cells (APCs), serving as critical signals for the adaptive immune system to distinguish malignant cells from healthy ones [1]. Because neoantigens are absent from the normal proteome, they are highly specific targets that bypass central tolerance, making them ideal for precision immunotherapy [2, 3]. Therapeutic strategies targeting these complexes include personalized cancer vaccines, such as mRNA-4157, which prime the immune system by presenting neoantigens on APCs, and TCR-engineered T-cell (TCR-T) therapies or bispecific engagers that directly target the complexes on tumor cells [1, 4]. These agents aim to induce or provide T-cell receptors (TCRs) that specifically recognize the unique peptide-MHC interface, leading to targeted destruction of cancer cells while sparing normal tissue [2, 5]. However, challenges such as HLA restriction, tumor heterogeneity, and immune evasion through MHC downregulation or loss of heterozygosity (LOH) in HLA alleles remain significant hurdles in the clinical application of these therapies [1, 6]. Citations: [1] Xie N, et al. Signal Transduct Target Ther. 2023;8(1):9. [2] Sahin U, et al. Nature. 2017;547(7662):222-226. [3] Schumacher TN, Schreiber RD. Science. 2015;348(6230):69-74. [4] Weber JS, et al. Lancet. 2024;403(10427):632-644. [5] Arnaud M, et al. Curr Opin Biotechnol. 2020;65:52-59. [6] McGranahan N, et al. Science. 2017;358(6367):1163-1167.

Other names

Neoepitope-MHC complexPeptide-HLA complexTumor-specific peptide-MHC complexTSA-MHC complexMutant peptide-MHC complexpMHC complex

The mechanism of action involves the specific recognition of the neoantigen-MHC complex by T-cell receptors (TCRs) or TCR-mimetic agents. In the case of vaccines, the target is presented by antigen-presenting cells to prime and expand neoantigen-specific T cells. For adoptive cell therapies and bispecific engagers, the drugs directly bind to the complex on tumor cells, inducing T-cell activation and subsequent granzyme/perforin-mediated lysis of the target cell.