Mutated Guanine nucleotide-binding protein G(s) subunit alpha (GNAS) neoantigen-MHC complex (Mutated GNAS neoantigen-MHC)

Mutated GNAS neoantigens presented by the Major Histocompatibility Complex (MHC) are highly specific targets for cancer immunotherapy. The GNAS gene encodes the alpha subunit of the stimulatory G protein (Gsα), which is essential for activating adenylyl cyclase and generating cAMP (UniProt P63092). Oncogenic hotspot mutations, particularly at the arginine 201 position (R201H, R201C), lead to constitutive signaling and are frequently found in pancreatic, appendiceal, and colorectal cancers (PubMed: 21775534). These mutations create neoepitopes—unique peptide sequences that are not present in the normal proteome. When these mutated peptides are presented by specific Human Leukocyte Antigen (HLA) molecules, such as HLA-A*01:01, they can be recognized by T-cell receptors (TCRs) (PubMed: 35921501). Therapeutic strategies targeting these complexes include TCR-engineered T-cell (TCR-T) therapies and personalized neoantigen vaccines. Because the target is derived from a somatic mutation, it offers high tumor specificity, potentially reducing the risk of off-tumor toxicity compared to traditional tumor-associated antigens. However, challenges remain, including the potential for immune escape through HLA downregulation or the loss of GNAS expression in tumor cells.

Other names

GNAS R201H neoantigenGNAS R201C neoantigenGNAS-mutant neoepitopeGNAS-derived HLA-restricted peptideMutated Gs-alpha neoantigen

Recognition of the mutated GNAS peptide-MHC complex by engineered or endogenous T-cell receptors (TCRs), triggering cytotoxic T-lymphocyte (CTL) mediated destruction of tumor cells.