Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA.

Animals Antigens, Neoplasm / genetics Class I Phosphatidylinositol 3-Kinases / genetics Humans Mice Mutation / genetics Neoplasms / genetics Receptors, Antigen, T-Cell

Journal

Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015

Informations de publication

Date de publication:
05 2022
Historique:
received: 02 04 2021
accepted: 16 03 2022
pubmed: 29 4 2022
medline: 21 5 2022
entrez: 28 4 2022
Statut: ppublish

Résumé

Public neoantigens (NeoAgs) represent an elite class of shared cancer-specific epitopes derived from recurrently mutated driver genes. Here we describe a high-throughput platform combining single-cell transcriptomic and T cell receptor (TCR) sequencing to establish whether mutant PIK3CA, among the most frequently genomically altered driver oncogenes, generates an immunogenic public NeoAg. Using this strategy, we developed a panel of TCRs that recognize an endogenously processed neopeptide encompassing a common PIK3CA hotspot mutation restricted by the prevalent human leukocyte antigen (HLA)-A*03:01 allele. Mechanistically, immunogenicity to this public NeoAg arises from enhanced neopeptide/HLA complex stability caused by a preferred HLA anchor substitution. Structural studies indicated that the HLA-bound neopeptide presents a comparatively 'featureless' surface dominated by the peptide's backbone. To bind this epitope with high specificity and affinity, we discovered that a lead TCR clinical candidate engages the neopeptide through an extended interface facilitated by an unusually long CDR3β loop. In patients with diverse malignancies, we observed NeoAg clonal conservation and spontaneous immunogenicity to the neoepitope. Finally, adoptive transfer of TCR-engineered T cells led to tumor regression in vivo in mice bearing PIK3CA-mutant tumors but not wild-type PIK3CA tumors. Together, these findings establish the immunogenicity and therapeutic potential of a mutant PIK3CA-derived public NeoAg.

Identifiants

DOI: 10.1038/s41591-022-01786-3 PMID: 35484264 PMC: PMC9117146
pubmed: 35484264
doi: 10.1038/s41591-022-01786-3
pii: 10.1038/s41591-022-01786-3
pmc: PMC9117146
doi:

Substances chimiques

Antigens, Neoplasm 0
Receptors, Antigen, T-Cell 0
Class I Phosphatidylinositol 3-Kinases EC 2.7.1.137
PIK3CA protein, human EC 2.7.1.137

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

946-957

Subventions

Organisme : NCI NIH HHS
ID : R35 CA241894
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR028976
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR025528
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI129543
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA259177
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIH HHS
ID : S10 OD021527
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA217694
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States

Informations de copyright

© 2022. The Author(s).

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Auteurs

Smita S Chandran (SS)

Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. chandrs1@mskcc.org.
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. chandrs1@mskcc.org.
Parker Institute for Cancer Immunotherapy, New York, NY, USA. chandrs1@mskcc.org.
ORCID: 0000-0001-9266-6878

Jiaqi Ma (J)

Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, IN, USA.
Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA.
ORCID: 0000-0002-6298-0193

Martin G Klatt (MG)

Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
ORCID: 0000-0001-8703-7305

Friederike Dündar (F)

Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA.
ORCID: 0000-0002-2301-112X

Chaitanya Bandlamudi (C)

Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Pedram Razavi (P)

Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA.
ORCID: 0000-0003-4236-0576

Hannah Y Wen (HY)

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Britta Weigelt (B)

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
ORCID: 0000-0001-9927-1270

Paul Zumbo (P)

Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA.

Si Ning Fu (SN)

Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Lauren B Banks (LB)

Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Fei Yi (F)

Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Enric Vercher (E)

Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Inaki Etxeberria (I)

Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
ORCID: 0000-0003-2713-0836

Watchain D Bestman (WD)

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Arnaud Da Cruz Paula (A)

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Ilinca S Aricescu (IS)

Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Alexander Drilon (A)

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA.
Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
ORCID: 0000-0001-6806-9061

Doron Betel (D)

Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA.
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA.
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
ORCID: 0000-0002-8006-7752

David A Scheinberg (DA)

Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Brian M Baker (BM)

Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, IN, USA.
Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA.

Christopher A Klebanoff (CA)

Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. klebanoc@mskcc.org.
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. klebanoc@mskcc.org.
Parker Institute for Cancer Immunotherapy, New York, NY, USA. klebanoc@mskcc.org.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. klebanoc@mskcc.org.
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA. klebanoc@mskcc.org.
Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. klebanoc@mskcc.org.
Cell Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. klebanoc@mskcc.org.
ORCID: 0000-0001-9645-3896

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Immunogenicity and therapeutic targeting of a...
questionsmedicales.fr › Facteurs biologiques › Antigènes › Antigènes néoplasiques › Immunogenicity and therapeutic targeting of a...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › Phosphatidylinositol-4-phosphate 3-kinase › Phosphatidylinositol 3-kinases de classe I › Immunogenicity and therapeutic targeting of a...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Immunogenicity and therapeutic targeting of a...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Immunogenicity and therapeutic targeting of a...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Immunogenicity and therapeutic targeting of a...
questionsmedicales.fr › Tumeurs › Immunogenicity and therapeutic targeting of a...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Récepteurs aux antigènes › Récepteurs aux antigènes des cellules T › Immunogenicity and therapeutic targeting of a...