Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy.

Details

Serval ID
serval:BIB_B490E5522790
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy.
Journal
Nature
Author(s)
Puig-Saus C., Sennino B., Peng S., Wang C.L., Pan Z., Yuen B., Purandare B., An D., Quach B.B., Nguyen D., Xia H., Jilani S., Shao K., McHugh C., Greer J., Peabody P., Nayak S., Hoover J., Said S., Jacoby K., Dalmas O., Foy S.P., Conroy A., Yi M.C., Shieh C., Lu W., Heeringa K., Ma Y., Chizari S., Pilling M.J., Ting M., Tunuguntla R., Sandoval S., Moot R., Hunter T., Zhao S., Saco J.D., Perez-Garcilazo I., Medina E., Vega-Crespo A., Baselga-Carretero I., Abril-Rodriguez G., Cherry G., Wong D.J., Hundal J., Chmielowski B., Speiser D.E., Bethune M.T., Bao X.R., Gros A., Griffith O.L., Griffith M., Heath J.R., Franzusoff A., Mandl S.J., Ribas A.
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Publication state
Published
Issued date
03/2023
Peer-reviewed
Oui
Volume
615
Number
7953
Pages
697-704
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells <sup>1-14</sup> . The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T cell responses in patients over their treatment course. Here we applied recently developed technologies <sup>15-17</sup> to capture neoantigen-specific T cells from blood and tumours from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. We generated personalized libraries of neoantigen-HLA capture reagents to single-cell isolate the T cells and clone their T cell receptors (neoTCRs). Multiple T cells with different neoTCR sequences (T cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These neoTCR clonotypes were recurrently detected over time in the blood and tumour. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T cell responses in the blood and tumour to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoTCRs in donor T cells using non-viral CRISPR-Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Thus, effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8 <sup>+</sup> T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.
Keywords
Humans, Antigens, Neoplasm/immunology, CD8-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/metabolism, Immunotherapy, Melanoma/drug therapy, Melanoma/genetics, Melanoma/immunology, Melanoma/pathology, Receptors, Antigen, T-Cell/immunology, Receptors, Antigen, T-Cell/metabolism, Immune Checkpoint Inhibitors/pharmacology, Immune Checkpoint Inhibitors/therapeutic use, HLA Antigens/immunology, Neoplasm Metastasis, Precision Medicine, Gene Editing, CRISPR-Cas Systems, Mutation
Pubmed
Web of science
Create date
13/03/2023 9:08
Last modification date
06/04/2023 5:53
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