Major Histocompatibility Complex class I and II molecules presenting tumor-specific frameshift peptides (MHC-FSP)

Major Histocompatibility Complex (MHC) class I and II molecules, also known as Human Leukocyte Antigens (HLA) in humans, are cell surface glycoproteins essential for the adaptive immune system. They function by presenting peptide fragments to T cell receptors (TCRs); MHC class I typically presents endogenous peptides to CD8+ cytotoxic T cells, while MHC class II presents exogenous or endosomal peptides to CD4+ helper T cells [1.4.1, 1.4.2]. In cancers characterized by mismatch repair deficiency (dMMR) and microsatellite instability (MSI), frameshift mutations occur frequently, leading to the production of novel, highly immunogenic "frameshift peptides" (FSPs) that are entirely absent from normal tissues [1.2.1, 1.2.5]. These FSPs are processed and presented by MHC molecules, forming a tumor-specific complex that serves as a potent target for immunotherapy [1.3.2, 1.5.1]. Therapeutic strategies, including neoantigen vaccines (mRNA, viral vectors, or peptides) and TCR-engineered T cell therapies, are designed to prime or enhance the immune response against these specific MHC-FSP complexes [1.1.2, 1.2.3]. By targeting these unique neoantigens, these therapies aim to achieve high specificity and reduce off-target toxicity, particularly in MSI-high colorectal, endometrial, and gastric cancers [1.2.1, 1.3.1].

Other names

HLA-FSP complexMHC-neoantigen complexFrameshift neoantigen-MHC complexpMHC complexTumor-specific frameshift peptide-HLA complexMHC-restricted frameshift neoantigens

Induction of neoantigen-specific T cell responses through the presentation of frameshift peptides to T cell receptors (TCRs) on CD4+ and CD8+ T cells, leading to targeted tumor cell lysis.