학술논문
Neoantigen-targeted CD8+T cell responses with PD-1 blockade therapy
Document Type
Article
Author
Puig-Saus, Cristina; Sennino, Barbara; Peng, Songming; Wang, Clifford L.; Pan, Zheng; Yuen, Benjamin; Purandare, Bhamini; An, Duo; Quach, Boi B.; Nguyen, Diana; Xia, Huiming; Jilani, Sameeha; Shao, Kevin; McHugh, Claire; Greer, John; Peabody, Phillip; Nayak, Saparya; Hoover, Jonathan; Said, Sara; Jacoby, Kyle; Dalmas, Olivier; Foy, Susan P.; Conroy, Andrew; Yi, Michael C.; Shieh, Christine; Lu, William; Heeringa, Katharine; Ma, Yan; Chizari, Shahab; Pilling, Melissa J.; Ting, Marc; Tunuguntla, Ramya; Sandoval, Salemiz; Moot, Robert; Hunter, Theresa; Zhao, Sidi; Saco, Justin D.; Perez-Garcilazo, Ivan; Medina, Egmidio; Vega-Crespo, Agustin; Baselga-Carretero, Ignacio; Abril-Rodriguez, Gabriel; Cherry, Grace; Wong, Deborah J.; Hundal, Jasreet; Chmielowski, Bartosz; Speiser, Daniel E.; Bethune, Michael T.; Bao, Xiaoyan R.; Gros, Alena; Griffith, Obi L.; Griffith, Malachi; Heath, James R.; Franzusoff, Alex; Mandl, Stefanie J.; Ribas, Antoni
Source
Nature; March 2023, Vol. 615 Issue: 7953 p697-704, 8p
Subject
Language
ISSN
00280836; 14764687
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 technologies15–17to 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.