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Neoantigen-targeted CD8 + T cell responses with PD-1 blockade therapy.
- Source :
-
Nature [Nature] 2023 Mar; Vol. 615 (7953), pp. 697-704. Date of Electronic Publication: 2023 Mar 08. - Publication Year :
- 2023
-
Abstract
- Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells <superscript>1-14</superscript> . 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 <superscript>15-17</superscript> 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 <superscript>+</superscript> T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.<br /> (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Humans
Receptors, Antigen, T-Cell immunology
Receptors, Antigen, T-Cell metabolism
HLA Antigens immunology
Neoplasm Metastasis
Precision Medicine
Gene Editing
CRISPR-Cas Systems
Mutation
Antigens, Neoplasm immunology
CD8-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes metabolism
Immunotherapy
Melanoma drug therapy
Melanoma genetics
Melanoma immunology
Melanoma pathology
Immune Checkpoint Inhibitors pharmacology
Immune Checkpoint Inhibitors therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 615
- Issue :
- 7953
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 36890230
- Full Text :
- https://doi.org/10.1038/s41586-023-05787-1