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

• Published in: Nature immunology Vol. 22; no. 6; pp. 735 - 745
• Main Authors: Bonnal, Raoul J. P., Rossetti, Grazisa, Lugli, Enrico, De Simone, Marco, Gruarin, Paola, Brummelman, Jolanda, Drufuca, Lorenzo, Passaro, Marco, Bason, Ramona, Gervasoni, Federica, Della Chiara, Giulia, D’Oria, Claudia, Martinovic, Martina, Curti, Serena, Ranzani, Valeria, Cordiglieri, Chiara, Alvisi, Giorgia, Mazza, Emilia Maria Cristina, Oliveto, Stefania, Silvestri, Ylenia, Carelli, Elena, Mazzara, Saveria, Bosotti, Roberto, Sarnicola, Maria Lucia, Godano, Chiara, Bevilacqua, Valeria, Lorenzo, Mariangela, Siena, Salvatore, Bonoldi, Emanuela, Sartore-Bianchi, Andrea, Amatu, Alessio, Veronesi, Giulia, Novellis, Pierluigi, Alloisio, Marco, Giani, Alessandro, Zucchini, Nicola, Opocher, Enrico, Ceretti, Andrea Pisani, Mariani, Nicolò, Biffo, Stefano, Prati, Daniele, Bardelli, Alberto, Geginat, Jens, Lanzavecchia, Antonio, Abrignani, Sergio, Pagani, Massimiliano
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2021; Nature Publishing Group
• Subjects: 631/250/2161; 631/67/580; Adult; Aged; Aged, 80 and over; Antitumor activity; Apoptosis; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer immunotherapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - secondary; Carcinoma, Non-Small-Cell Lung - therapy; CD4 antigen; Cell death; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Proliferation - genetics; Chemotherapy, Adjuvant - methods; Chitinase; Chitinases - metabolism; Clonal Hematopoiesis - immunology; Colectomy; Colon - pathology; Colon - surgery; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - pathology; Colorectal Neoplasms - therapy; Datasets as Topic; Disease Progression; Drug Resistance, Neoplasm - immunology; Effector cells; Female; Flow Cytometry; Forkhead protein; Forkhead Transcription Factors - metabolism; Gene Expression Regulation, Neoplastic - immunology; Granzymes - metabolism; Heterogeneity; Humans; Immune checkpoint; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunology; Immunotherapy; Infectious Diseases; Kaplan-Meier Estimate; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Lymphocytes T; Male; Metastases; Metastasis; Middle Aged; Non-small cell lung carcinoma; PD-1 protein; Primary Cell Culture; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Proteins; RNA-Seq; Single-Cell Analysis; T-Box Domain Proteins - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tumors
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-021-00930-4

Regulatory T (T reg ) 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 + T reg 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 T reg 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 T reg cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy. Human primary and metastatic tumors harbor CD4 + T reg cells that can suppress antitumor immune responses. Bonnal et al. identify an intratumoral type 1 T reg -like CD4 + T cell subset that expresses the transcription factor EOMES, granzyme K and CHI3L2. This EOMES + T cell subset correlates with disease progression but is responsive to PD-1 checkpoint blockade immunotherapy.