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

Cristina Puig-Saus, Barbara Sennino, Songming Peng, Clifford L. Wang, Zheng Pan, Benjamin Yuen, Bhamini Purandare, Duo An, Boi B. Quach, Diana Nguyen, Huiming Xia, Sameeha Jilani, Kevin Shao, Claire McHugh, John Greer, Phillip Peabody, Saparya Nayak, Jonathan Hoover, Sara Said, Kyle JacobyOlivier Dalmas, Susan P. Foy, Andrew Conroy, Michael C. Yi, Christine Shieh, William Lu, Katharine Heeringa, Yan Ma, Shahab Chizari, Melissa J. Pilling, Marc Ting, Ramya Tunuguntla, Salemiz Sandoval, Robert Moot, Theresa Hunter, Sidi Zhao, Justin D. Saco, Ivan Perez-Garcilazo, Egmidio Medina, Agustin Vega-Crespo, Ignacio Baselga-Carretero, Gabriel Abril-Rodriguez, Grace Cherry, Deborah J. Wong, Jasreet Hundal, Bartosz Chmielowski, Daniel E. Speiser, Michael T. Bethune, Xiaoyan R. Bao, Alena Gros, Obi L. Griffith, Malachi Griffith, James R. Heath, Alex Franzusoff, Stefanie J. Mandl, Antoni Ribas

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

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

Original languageEnglish
Pages (from-to)697-704
Number of pages8
JournalNature
Volume615
Issue number7953
DOIs
StatePublished - Mar 23 2023

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