9wk0
Neoantigen Rac1P29S-HLA-A2
Structural highlights
FunctionPublication Abstract from PubMedT cell receptor (TCR)-based immunotherapy can drive cancer regression by targeting neoantigens derived from mutations in self-proteins. Most neoantigens result from mutations in solvent-exposed residues creating neoepitopes that allow highly specific TCR recognition. Here, we describe a melanoma neoantigen (Rac1(P29S)) caused by a mutation at a primary anchor residue. Unlike typical cases, the immunogenicity of Rac1(P29S) stems from this anchor mutation, which permits MHC presentation of the mutant peptide but not the wild-type counterpart. We determined the structures of both the mutant Rac1(P29S)-HLA-A2 complex and its complex with the tumor-specific TCR 5934. These structures show how the P29S mutation makes a Rac1 self- peptide visible to T cells. Notably, TCR 5934 primarily engages the C-terminal, non-mutated P8 threonine residue of Rac1(P29S) -far from the N-terminal mutated P2 serine. This contrasts with most neoantigen-specific TCRs, which typically focus on the mutated residue to distinguish mutant from wild-type peptides. Together, these findings provide a structural framework to guide the development of TCR-based cancer immunotherapies. Structural basis for TCR recognition of a Rac1 neoantigen arising from anchor residue mutation.,Zeng Y, Yang D, Zhao J, Yuan P, Jin H, Liao W, Chen G, Wu D J Struct Biol. 2026 May 25;218(3):108329. doi: 10.1016/j.jsb.2026.108329. PMID:42190883[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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