Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity.

Autor:	Ma J; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA., Ayres CM; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA., Brambley CA; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA., Chandran SS; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.; Center for Cell Engineering, MSKCC, New York, NY, USA., Rosales TJ; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA., Corcelli SA; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA., Kovrigin EL; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA., Klebanoff CA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.; Center for Cell Engineering, MSKCC, New York, NY, USA.; Weill Cornell Medical College, New York, NY, USA.; Parker Institute for Cancer Immunotherapy, New York, NY, USA., Baker BM; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 May 29. Date of Electronic Publication: 2024 May 29.
DOI:	10.21203/rs.3.rs-4457195/v1
Abstrakt:	The inherent cross-reactivity of the T cell receptor (TCR) is balanced by high specificity, which often manifests in confounding ways not easily interpretable from static structures. We show here that TCR discrimination between an HLA-A*03:01 (HLA-A3)-restricted public neoantigen derived from mutant PIK3CA and its wild-type (WT) counterpart emerges from motions within the HLA binding groove that vary with the identity of the peptide's first primary anchor. The motions form a dynamic gate that in the complex with the WT peptide impedes a large conformational change required for TCR binding. The more rigid neoantigen is insusceptible to this limiting dynamic, and with the gate open, is able to transit its central tryptophan residue underneath the peptide backbone to the contralateral side of the HLA-A3 peptide binding groove, facilitating TCR binding. Our findings reveal a novel mechanism driving TCR specificity for a cancer neoantigen that is rooted in the dynamic and allosteric nature of peptide/MHC-I complexes, with implications for resolving long-standing and often confounding questions about the determinants of T cell specificity. Competing Interests: Additional Declarations: Yes there is potential Competing Interest. C.A.K. and S.S.C. are inventors on patents related to the T cell receptor (TCR) sequences featured in this manuscript and are recipients of licensing revenue from Intima Bioscience shared according to Memorial Sloan Kettering Cancer Center (MSKCC) institutional policies. C.A.K. has consulted for or is on the scientific advisory boards for Achilles Therapeutics, Affini-T Therapeutics, Aleta BioTherapeutics, Bellicum Pharmaceuticals, Bristol Myers Squibb, Catamaran Bio, Cell Design Labs, Decheng Capital, G1 Therapeutics, Klus Pharma, Obsidian Therapeutics, PACT Pharma, Roche/Genentech, Royalty Pharma, and T-knife, and is a scientific co-founder and equity holder in Affini-T Therapeutics. S.S.C. is a scientific advisor and equity holder in Affini-T Therapeutics. B.M.B. is an inventor on patents relating to differences between mutant and self in identifying immunogenic neoantigens, and is on the scientitic advisory board or has consulted for Merck & Co., Pfizer, T-cure Bioscience, Eureka Therapeutics, and EnaraBio. Conflicts of interest statement C.A.K. and S.S.C. are inventors on patents related to the T cell receptor (TCR) sequences featured in this manuscript and are recipients of licensing revenue from Intima Bioscience shared according to Memorial Sloan Kettering Cancer Center (MSKCC) institutional policies. C.A.K. has consulted for or is on the scientific advisory boards for Achilles Therapeutics, Affini-T Therapeutics, Aleta BioTherapeutics, Bellicum Pharmaceuticals, Bristol Myers Squibb, Catamaran Bio, Cell Design Labs, Decheng Capital, G1 Therapeutics, Klus Pharma, Obsidian Therapeutics, PACT Pharma, Roche/Genentech, Royalty Pharma, and T-knife, and is a scientific co-founder and equity holder in Affini-T Therapeutics. S.S.C. is a scientific advisor and equity holder in Affini-T Therapeutics. B.M.B. is an inventor on patents relating to differences between mutant and self in identifying immunogenic neoantigens, and is on the scientific advisory board or has consulted for Merck & Co., Pfizer, T-cure Bioscience, Eureka Therapeutics, and EnaraBio.
Databáze:	MEDLINE
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