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
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
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