Patient-specific neoantigen peptide–Major Histocompatibility Complex (pMHC) (Neoantigen-MHC)

Patient-specific neoantigen peptide–Major Histocompatibility Complex (pMHC) complexes are unique molecular targets formed by the presentation of tumor-specific mutated peptides on the surface of cancer cells via Human Leukocyte Antigen (HLA) molecules (Sahin & Türeci, 2018). These complexes are highly specific to individual patients due to the random nature of somatic mutations and the diversity of HLA alleles, making them ideal targets for precision immunotherapy (Yarchoan et al., 2017). In the context of tumor-infiltrating lymphocytes (TILs), recent research has identified KLF2 (Kruppel-like factor 2) as a key transcription factor that is significantly overexpressed in T cells that specifically recognize these neoantigen-MHC complexes (Lowery et al., 2022). This discovery allows for the identification and enrichment of neoantigen-reactive TCRs for use in adoptive cell therapies. Targeting these complexes via TCR-engineered T cells or personalized mRNA vaccines aims to induce a potent and specific immune response against the tumor while minimizing damage to healthy tissues. However, therapeutic challenges remain, including the potential for tumor escape through HLA downregulation and the risk of off-target cross-reactivity with self-antigens that may share structural similarities with the neoantigen.

Other names

Neoantigen-HLA complexpMHC complexTumor-specific antigen-MHC complexNeoepitope-MHC complexTumor-specific neoantigen-HLA complex

Recognition of the specific peptide-MHC complex by a cognate T-cell receptor (TCR) leads to the formation of an immunological synapse, activation of the CD3 signaling complex, and subsequent release of cytotoxic molecules like perforin and granzymes to induce tumor cell apoptosis.