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

R.J.P. Bonnal, G. Rossetti, E. Lugli, M. De Simone, P. Gruarin, J. Brummelman, L. Drufuca, M. Passaro, R. Bason, F. Gervasoni, G. Della Chiara, C. D’Oria, M. Martinovic, S. Curti, V. Ranzani, C. Cordiglieri, G. Alvisi, E.M.C. Mazza, S. Oliveto, Y. SilvestriE. Carelli, S. Mazzara, R. Bosotti, M.L. Sarnicola, C. Godano, V. Bevilacqua, M. Lorenzo, S. Siena, E. Bonoldi, A. Sartore-Bianchi, A. Amatu, G. Veronesi, P. Novellis, M. Alloisio, A. Giani, N. Zucchini, E. Opocher, A.P. Ceretti, N. Mariani, S. Biffo, D. Prati, A. Bardelli, J. Geginat, A. Lanzavecchia, S. Abrignani, M. 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 - 2021


  • chitinase 3 like protein 2
  • eomesodermin
  • glycosidase
  • granzyme
  • granzyme K
  • interleukin 10
  • interleukin 12
  • interleukin 27
  • programmed death 1 ligand 1
  • programmed death 1 receptor
  • transcription factor FOXP3
  • unclassified drug
  • CHI3L2 protein, human
  • chitinase
  • EOMES protein, human
  • forkhead transcription factor
  • FOXP3 protein, human
  • GZMK protein, human
  • PDCD1 protein, human
  • T box transcription factor
  • Article
  • bile duct carcinoma
  • cancer growth
  • cancer immunotherapy
  • CD4+ T lymphocyte
  • CD8+ T lymphocyte
  • cell clone
  • cell cloning
  • cell expansion
  • cell function
  • cell size
  • controlled study
  • cytokine production
  • flow cytometry
  • gene expression
  • human
  • human cell
  • human tissue
  • in vitro study
  • lymphocyte differentiation
  • lymphocyte proliferation
  • lymphocytic infiltration
  • metastasis
  • metastatic colorectal cancer
  • non small cell lung cancer
  • primary tumor
  • progression free survival
  • regulatory T lymphocyte
  • RNA sequencing
  • single cell analysis
  • single cell RNA seq
  • survival rate
  • T lymphocyte subpopulation
  • Th1 cell
  • transcriptomics
  • treatment response
  • tumor associated leukocyte
  • tumor microenvironment
  • adjuvant chemotherapy
  • adult
  • aged
  • cell differentiation
  • cell proliferation
  • colon
  • colon resection
  • colorectal tumor
  • disease exacerbation
  • drug resistance
  • drug therapy
  • female
  • gene expression regulation
  • genetics
  • immunology
  • information processing
  • Kaplan Meier method
  • lung tumor
  • male
  • metabolism
  • middle aged
  • pathology
  • pharmacology
  • primary cell culture
  • procedures
  • surgery
  • very elderly
  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Non-Small-Cell Lung
  • Cell Differentiation
  • Cell Proliferation
  • Chemotherapy, Adjuvant
  • Chitinases
  • Clonal Hematopoiesis
  • Colectomy
  • Colon
  • Colorectal Neoplasms
  • Datasets as Topic
  • Disease Progression
  • Drug Resistance, Neoplasm
  • Female
  • Flow Cytometry
  • Forkhead Transcription Factors
  • Gene Expression Regulation, Neoplastic
  • Granzymes
  • Humans
  • Immune Checkpoint Inhibitors
  • Kaplan-Meier Estimate
  • Lung Neoplasms
  • Male
  • Middle Aged
  • Primary Cell Culture
  • Programmed Cell Death 1 Receptor
  • RNA-Seq
  • Single-Cell Analysis
  • T-Box Domain Proteins
  • T-Lymphocytes, Regulatory


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