Molecular mechanism of phosphopeptide neoantigen immunogenicity

Yury Patskovsky, Aswin Natarajan, Larysa Patskovska, Samantha Nyovanie, Bishnu Joshi, Benjamin Morin, Christine Brittsan, Olivia Huber, Samuel Gordon, Xavier Michelet, Florian Schmitzberger, Robert B. Stein, Mark A. Findeis, Andy Hurwitz, Marc Dijk, Eleni Chantzoura, Alvaro S. Yague, Daniel Pollack Smith, Jennifer S. Buell, Dennis Underwood () and Michelle Krogsgaard ()
Additional contact information
Yury Patskovsky: New York University Grossman School of Medicine
Aswin Natarajan: New York University Grossman School of Medicine
Larysa Patskovska: New York University Grossman School of Medicine
Samantha Nyovanie: New York University Grossman School of Medicine
Bishnu Joshi: Agenus
Benjamin Morin: Agenus
Christine Brittsan: Agenus
Olivia Huber: Agenus
Samuel Gordon: Agenus
Xavier Michelet: Agenus
Florian Schmitzberger: Agenus
Robert B. Stein: Agenus
Mark A. Findeis: Agenus
Andy Hurwitz: Agenus
Marc Dijk: Agenus
Eleni Chantzoura: Agenus
Alvaro S. Yague: Agenus
Daniel Pollack Smith: Agenus
Jennifer S. Buell: Agenus
Dennis Underwood: Agenus
Michelle Krogsgaard: New York University Grossman School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen, pMLL747–755 (EPR(pS)PSHSM), is recognized by a cognate T cell receptor named TCR27, a candidate for cancer immunotherapy. We show that the replacement of phosphoserine P4 with serine or phosphomimetics does not affect pMHC conformation or peptide-MHC affinity but abrogates TCR27-dependent T cell activation and weakens binding between TCR27 and pMHC. Here we describe the crystal structures for TCR27 and cognate pMHC, map of the interface produced by nuclear magnetic resonance, and a ternary complex generated using information-driven protein docking. Our data show that non-covalent interactions between the epitope phosphate group and TCR27 are crucial for TCR specificity. This study supports development of new treatment options for cancer patients through target expansion and TCR optimization.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39425-1

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DOI: 10.1038/s41467-023-39425-1

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