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Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy
- 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
- et al.
Published Web Location
https://doi.org/10.1038/s41586-023-05787-1Abstract
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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