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Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy.
- Source :
- Nature; Mar2023, Vol. 615 Issue 7953, p697-704, 8p
- Publication Year :
- 2023
-
Abstract
- Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells1–14. 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 technologies15–17 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.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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00280836
- Volume :
- 615
- Issue :
- 7953
- Database :
- Complementary Index
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 162717802
- Full Text :
- https://doi.org/10.1038/s41586-023-05787-1