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. Silvestri; E. 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

doi:10.1038/s41590-021-00930-4

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 journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	735-745
Number of pages	11
Journal	Nature Immunology
Volume	22
Issue number	6
DOIs	https://doi.org/10.1038/s41590-021-00930-4
Publication status	Published - 2021

Keywords

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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10.1038/s41590-021-00930-4

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85106235989&doi=10.1038%2fs41590-021-00930-4&partnerID=40&md5=887e92f8a61f500167ef0259f1147b43

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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(6), 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, no. 6, 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 (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.",

keywords = "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",

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

note = "Export Date: 10 February 2022 CODEN: NIAMC Correspondence Address: Geginat, J.; Istituto Nazionale Genetica Molecolare Romeo ed Enrica InvernizziItaly; email: geginat@ingm.org Correspondence Address: Lanzavecchia, A.; Istituto Nazionale Genetica Molecolare Romeo ed Enrica InvernizziItaly; email: lanzavecchia@ingm.org Correspondence Address: Abrignani, S.; Istituto Nazionale Genetica Molecolare Romeo ed Enrica InvernizziItaly; email: abrignani@ingm.org Correspondence Address: Pagani, M.; Istituto Nazionale Genetica Molecolare Romeo ed Enrica InvernizziItaly; email: massimiliano.pagani@ifom.eu",

year = "2021",

doi = "10.1038/s41590-021-00930-4",

language = "English",

volume = "22",

pages = "735--745",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Research",

number = "6",

}

TY - JOUR

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

AU - Bonnal, R.J.P.

AU - Rossetti, G.

AU - Lugli, E.

AU - De Simone, M.

AU - Gruarin, P.

AU - Brummelman, J.

AU - Drufuca, L.

AU - Passaro, M.

AU - Bason, R.

AU - Gervasoni, F.

AU - Della Chiara, G.

AU - D’Oria, C.

AU - Martinovic, M.

AU - Curti, S.

AU - Ranzani, V.

AU - Cordiglieri, C.

AU - Alvisi, G.

AU - Mazza, E.M.C.

AU - Oliveto, S.

AU - Silvestri, Y.

AU - Carelli, E.

AU - Mazzara, S.

AU - Bosotti, R.

AU - Sarnicola, M.L.

AU - Godano, C.

AU - Bevilacqua, V.

AU - Lorenzo, M.

AU - Siena, S.

AU - Bonoldi, E.

AU - Sartore-Bianchi, A.

AU - Amatu, A.

AU - Veronesi, G.

AU - Novellis, P.

AU - Alloisio, M.

AU - Giani, A.

AU - Zucchini, N.

AU - Opocher, E.

AU - Ceretti, A.P.

AU - Mariani, N.

AU - Biffo, S.

AU - Prati, D.

AU - Bardelli, A.

AU - Geginat, J.

AU - Lanzavecchia, A.

AU - Abrignani, S.

AU - Pagani, M.

N1 - Export Date: 10 February 2022 CODEN: NIAMC Correspondence Address: Geginat, J.; Istituto Nazionale Genetica Molecolare Romeo ed Enrica InvernizziItaly; email: geginat@ingm.org Correspondence Address: Lanzavecchia, A.; Istituto Nazionale Genetica Molecolare Romeo ed Enrica InvernizziItaly; email: lanzavecchia@ingm.org Correspondence Address: Abrignani, S.; Istituto Nazionale Genetica Molecolare Romeo ed Enrica InvernizziItaly; email: abrignani@ingm.org Correspondence Address: Pagani, M.; Istituto Nazionale Genetica Molecolare Romeo ed Enrica InvernizziItaly; email: massimiliano.pagani@ifom.eu

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - chitinase 3 like protein 2

KW - eomesodermin

KW - glycosidase

KW - granzyme

KW - granzyme K

KW - interleukin 10

KW - interleukin 12

KW - interleukin 27

KW - programmed death 1 ligand 1

KW - programmed death 1 receptor

KW - transcription factor FOXP3

KW - unclassified drug

KW - CHI3L2 protein, human

KW - chitinase

KW - EOMES protein, human

KW - forkhead transcription factor

KW - FOXP3 protein, human

KW - GZMK protein, human

KW - PDCD1 protein, human

KW - T box transcription factor

KW - Article

KW - bile duct carcinoma

KW - cancer growth

KW - cancer immunotherapy

KW - CD4+ T lymphocyte

KW - CD8+ T lymphocyte

KW - cell clone

KW - cell cloning

KW - cell expansion

KW - cell function

KW - cell size

KW - controlled study

KW - cytokine production

KW - flow cytometry

KW - gene expression

KW - human

KW - human cell

KW - human tissue

KW - in vitro study

KW - lymphocyte differentiation

KW - lymphocyte proliferation

KW - lymphocytic infiltration

KW - metastasis

KW - metastatic colorectal cancer

KW - non small cell lung cancer

KW - primary tumor

KW - progression free survival

KW - regulatory T lymphocyte

KW - RNA sequencing

KW - single cell analysis

KW - single cell RNA seq

KW - survival rate

KW - T lymphocyte subpopulation

KW - Th1 cell

KW - transcriptomics

KW - treatment response

KW - tumor associated leukocyte

KW - tumor microenvironment

KW - adjuvant chemotherapy

KW - adult

KW - aged

KW - cell differentiation

KW - cell proliferation

KW - colon

KW - colon resection

KW - colorectal tumor

KW - disease exacerbation

KW - drug resistance

KW - drug therapy

KW - female

KW - gene expression regulation

KW - genetics

KW - immunology

KW - information processing

KW - Kaplan Meier method

KW - lung tumor

KW - male

KW - metabolism

KW - middle aged

KW - pathology

KW - pharmacology

KW - primary cell culture

KW - procedures

KW - surgery

KW - very elderly

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Carcinoma, Non-Small-Cell Lung

KW - Cell Differentiation

KW - Cell Proliferation

KW - Chemotherapy, Adjuvant

KW - Chitinases

KW - Clonal Hematopoiesis

KW - Colectomy

KW - Colon

KW - Colorectal Neoplasms

KW - Datasets as Topic

KW - Disease Progression

KW - Drug Resistance, Neoplasm

KW - Female

KW - Flow Cytometry

KW - Forkhead Transcription Factors

KW - Gene Expression Regulation, Neoplastic

KW - Granzymes

KW - Humans

KW - Immune Checkpoint Inhibitors

KW - Kaplan-Meier Estimate

KW - Lung Neoplasms

KW - Male

KW - Middle Aged

KW - Primary Cell Culture

KW - Programmed Cell Death 1 Receptor

KW - RNA-Seq

KW - Single-Cell Analysis

KW - T-Box Domain Proteins

KW - T-Lymphocytes, Regulatory

U2 - 10.1038/s41590-021-00930-4

DO - 10.1038/s41590-021-00930-4

M3 - Article

SN - 1529-2908

VL - 22

SP - 735

EP - 745

JO - Nature Immunology

JF - Nature Immunology

IS - 6

ER -

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

Abstract

Keywords

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