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 Silvestri; Elena 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

doi:10.1038/s41590-021-00930-4

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

Istituto Oncologico Candiolo

Research output: Contribution to journal › Article › peer-review

Abstract

Regulatory T (T ) 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 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 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 cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy.

Original language	Undefined/Unknown
Pages (from-to)	735-745
Number of pages	11
Journal	Nature Immunology
Volume	22
DOIs	https://doi.org/10.1038/s41590-021-00930-4
Publication status	Published - Jun 1 2021

Keywords

Adult
Aged
80 and over
Carcinoma
Non-Small-Cell Lung
genetics
immunology
secondary
therapy
Cell Differentiation
Cell Proliferation
Chemotherapy
Adjuvant
methods
Chitinases
metabolism
Clonal Hematopoiesis
Colectomy
Colon
pathology
surgery
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
pharmacology
therapeutic use
Kaplan-Meier Estimate
Lung Neoplasms
Male
Middle Aged
Primary Cell Culture
Programmed Cell Death 1 Receptor
antagonists & inhibitors
RNA-Seq
Single-Cell Analysis
T-Box Domain Proteins
T-Lymphocytes
Regulatory

Access to Document

10.1038/s41590-021-00930-4

Cite this

Bonnal, R. J. P., Rossetti, G., Lugli, E., De Simone, M., Gruarin, P., Brummelman, J., Drufuca, L., Passaro, M., Bason, R., Gervasoni, F., Della Chiara, G., D'Oria, C., Martinovic, M., Curti, S., Ranzani, V., Cordiglieri, C., Alvisi, G., Mazza, E. M. C., Oliveto, S., ... Pagani, M. (2021). Clonally expanded EOMES + Tr1-like cells in primary and metastatic tumors are associated with disease progression. Nature Immunology, 22, 735-745. https://doi.org/10.1038/s41590-021-00930-4

Bonnal, RJP, Rossetti, G, Lugli, E, De Simone, M, Gruarin, P, Brummelman, J, Drufuca, L, Passaro, M, Bason, R, Gervasoni, F, Della Chiara, G, D'Oria, C, Martinovic, M, Curti, S, Ranzani, V, Cordiglieri, C, Alvisi, G, Mazza, EMC, Oliveto, S, Silvestri, Y, Carelli, E, Mazzara, S, Bosotti, R, Sarnicola, ML, Godano, C, Bevilacqua, V, Lorenzo, M, Siena, S, Bonoldi, E, Sartore-Bianchi, A, Amatu, A, Veronesi, G, Novellis, P, Alloisio, M, Giani, A, Zucchini, N, Opocher, E, Ceretti, AP, Mariani, N, Biffo, S, Prati, D, Bardelli, A, Geginat, J, Lanzavecchia, A, Abrignani, S & Pagani, M 2021, 'Clonally expanded EOMES + Tr1-like cells in primary and metastatic tumors are associated with disease progression.', Nature Immunology, vol. 22, pp. 735-745. https://doi.org/10.1038/s41590-021-00930-4

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title = "Clonally expanded EOMES + Tr1-like cells in primary and metastatic tumors are associated with disease progression.",

abstract = "Regulatory T (T ) 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 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 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 cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy.",

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T1 - Clonally expanded EOMES + Tr1-like cells in primary and metastatic tumors are associated with disease progression.

AU - Bonnal, Raoul J. P.

AU - Rossetti, Grazisa

AU - Lugli, Enrico

AU - De Simone, Marco

AU - Gruarin, Paola

AU - Brummelman, Jolanda

AU - Drufuca, Lorenzo

AU - Passaro, Marco

AU - Bason, Ramona

AU - Gervasoni, Federica

AU - Della Chiara, Giulia

AU - D'Oria, Claudia

AU - Martinovic, Martina

AU - Curti, Serena

AU - Ranzani, Valeria

AU - Cordiglieri, Chiara

AU - Alvisi, Giorgia

AU - Mazza, Emilia Maria Cristina

AU - Oliveto, Stefania

AU - Silvestri, Ylenia

AU - Carelli, Elena

AU - Mazzara, Saveria

AU - Bosotti, Roberto

AU - Sarnicola, Maria Lucia

AU - Godano, Chiara

AU - Bevilacqua, Valeria

AU - Lorenzo, Mariangela

AU - Siena, Salvatore

AU - Bonoldi, Emanuela

AU - Sartore-Bianchi, Andrea

AU - Amatu, Alessio

AU - Veronesi, Giulia

AU - Novellis, Pierluigi

AU - Alloisio, Marco

AU - Giani, Alessandro

AU - Zucchini, Nicola

AU - Opocher, Enrico

AU - Ceretti, Andrea Pisani

AU - Mariani, Nicolò

AU - Biffo, Stefano

AU - Prati, Daniele

AU - Bardelli, Alberto

AU - Geginat, Jens

AU - Lanzavecchia, Antonio

AU - Abrignani, Sergio

AU - Pagani, Massimiliano

PY - 2021/6/1

Y1 - 2021/6/1

N2 - Regulatory T (T ) 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 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 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 cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy.

AB - Regulatory T (T ) 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 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 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 cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy.

KW - Adult

KW - Aged

KW - 80 and over

KW - Carcinoma

KW - Non-Small-Cell Lung

KW - genetics

KW - immunology

KW - secondary

KW - therapy

KW - Cell Differentiation

KW - Cell Proliferation

KW - Chemotherapy

KW - Adjuvant

KW - methods

KW - Chitinases

KW - metabolism

KW - Clonal Hematopoiesis

KW - Colectomy

KW - Colon

KW - pathology

KW - surgery

KW - Colorectal Neoplasms

KW - Datasets as Topic

KW - Disease Progression

KW - Drug Resistance

KW - Neoplasm

KW - Female

KW - Flow Cytometry

KW - Forkhead Transcription Factors

KW - Gene Expression Regulation

KW - Neoplastic

KW - Granzymes

KW - Humans

KW - Immune Checkpoint Inhibitors

KW - pharmacology

KW - therapeutic use

KW - Kaplan-Meier Estimate

KW - Lung Neoplasms

KW - Male

KW - Middle Aged

KW - Primary Cell Culture

KW - Programmed Cell Death 1 Receptor

KW - antagonists & inhibitors

KW - RNA-Seq

KW - Single-Cell Analysis

KW - T-Box Domain Proteins

KW - T-Lymphocytes

KW - Regulatory

U2 - 10.1038/s41590-021-00930-4

DO - 10.1038/s41590-021-00930-4

M3 - Articolo

SN - 1529-2908

VL - 22

SP - 735

EP - 745

JO - Nature Immunology

JF - Nature Immunology

ER -