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

CD8型 免疫疗法 T细胞受体 T细胞 免疫学 细胞毒性T细胞 生物 人类白细胞抗原 黑色素瘤 抗原 癌症研究 免疫系统 遗传学 体外
作者
Cristina Puig-Saus,Barbara Sennino,Songming Peng,Clifford L. Wang,Zheng Pan,Benjamin Yuen,Bhamini Purandare,Duo An,Boi Quach,Diana Nguyen,Huiming Xia,Sameeha Jilani,Kevin Shao,Claire McHugh,John P. Greer,Phillip Peabody,Saparya Nayak,Jonathan Hoover,Sara Said,Kyle Jacoby
出处
期刊:Nature [Nature Portfolio]
卷期号:615 (7953): 697-704 被引量:110
标识
DOI:10.1038/s41586-023-05787-1
摘要

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+ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.
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