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

Authors :
Puig-Saus C
Sennino B
Peng S
Wang CL
Pan Z
Yuen B
Purandare B
An D
Quach BB
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 SP
Conroy A
Yi MC
Shieh C
Lu W
Heeringa K
Ma Y
Chizari S
Pilling MJ
Ting M
Tunuguntla R
Sandoval S
Moot R
Hunter T
Zhao S
Saco JD
Perez-Garcilazo I
Medina E
Vega-Crespo A
Baselga-Carretero I
Abril-Rodriguez G
Cherry G
Wong DJ
Hundal J
Chmielowski B
Speiser DE
Bethune MT
Bao XR
Gros A
Griffith OL
Griffith M
Heath JR
Franzusoff A
Mandl SJ
Ribas A
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.)

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