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Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8 + T-myeloid cell networks in melanoma

2024; American Association for the Advancement of Science; Volume: 9; Issue: 92 Linguagem: Inglês

10.1126/sciimmunol.adg7995

2470-9468

David Barras, Eleonora Ghisoni, Johanna Chiffelle, Angela Orcurto, Julien Dagher, Noémie Fahr, Fabrizio Benedetti, Isaac Crespo, Alizée J. Grimm, Matteo Morotti, Stefan Zimmermann, Rafael Durán, Martina Imbimbo, Maria Ochoa de Olza, Blanca Navarro, Krisztián Homicskó, Sara Bobisse, Danny Labes, Zoe Tsourti, Charitini Andriakopoulou, Fernanda G. Herrera, Rémy Pétremand, Reinhard Dummer, Grégoire Berthod, Anne I. Kraemer, Florian Huber, Jonathan Thévenet, Michal Bassani‐Sternberg, Niklaus Schaefer, John O. Prior, Maurice Matter, Veronica Aedo, Clarisse Dromain, Jesús Corría-Osorio, Stéphanie Tissot, Lana E. Kandalaft, Raphaël Gottardo, Mikaël J. Pittet, Christine Sempoux, Olivier Michielin, Urania Dafni, Lionel Trueb, Alexandre Harari, Denarda Dangaj, George Coukos,

Single-cell and spatial transcriptomics

Adoptive cell therapy (ACT) using ex vivo–expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell–intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8 + TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor–reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network–based biomarkers that could improve patient selection and guide the design of ACT clinical trials.