Clonally expanded EOMES+ Tr1-like cells in primary and metastatic tumors are associated with disease progression

Raoul J.P. Bonnal, Grazisa Rossetti, Enrico Lugli, Marco De Simone, Paola Gruarin, Jolanda Brummelman, Lorenzo Drufuca, Marco Passaro, Ramona Bason, Federica Gervasoni, Giulia Della Chiara, Claudia D’Oria, Martina Martinovic, Serena Curti, Valeria Ranzani, Chiara Cordiglieri, Giorgia Alvisi, Emilia Maria Cristina Mazza, Stefania Oliveto, Ylenia SilvestriElena Carelli, Saveria Mazzara, Roberto Bosotti, Maria Lucia Sarnicola, Chiara Godano, Valeria Bevilacqua, Mariangela Lorenzo, Salvatore Siena, Emanuela Bonoldi, Andrea Sartore-Bianchi, Alessio Amatu, Giulia Veronesi, Pierluigi Novellis, Marco Alloisio, Alessandro Giani, Nicola Zucchini, Enrico Opocher, Andrea Pisani Ceretti, Nicolò Mariani, Stefano Biffo, Daniele Prati, Alberto Bardelli, Jens Geginat, Antonio Lanzavecchia, Sergio Abrignani, Massimiliano Pagani

Research output: Contribution to journalArticlepeer-review


Regulatory T (Treg) cells are a barrier for tumor immunity and a target for immunotherapy. Using single-cell transcriptomics, we found that CD4+ T cells infiltrating primary and metastatic colorectal cancer and non-small-cell lung cancer are highly enriched for two subsets of comparable size and suppressor function comprising forkhead box protein P3+ Treg and eomesodermin homolog (EOMES)+ type 1 regulatory T (Tr1)-like cells also expressing granzyme K and chitinase-3-like protein 2. EOMES+ Tr1-like cells, but not Treg cells, were clonally related to effector T cells and were clonally expanded in primary and metastatic tumors, which is consistent with their proliferation and differentiation in situ. Using chitinase-3-like protein 2 as a subset signature, we found that the EOMES+ Tr1-like subset correlates with disease progression but is also associated with response to programmed cell death protein 1–targeted immunotherapy. Collectively, these findings highlight the heterogeneity of Treg cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy.

Original languageEnglish
Pages (from-to)735-745
Number of pages11
JournalNature Immunology
Issue number6
Publication statusPublished - Jun 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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