By analyzing CD4+ T cells from CRC and NSCLC primary tumors and metastases, Bonnal
et al. showed intratumoral enrichment of clonotypically distinct Foxp3+ Treg cells and Eomes+granzyme K+ Foxp3- type 1 regulatory T (Tr1)-like cells. Both subsets were also shown in melanoma, breast, and liver tumors. Tr1-like cells expressed PD-1 and chitinase-3-like protein 2 (CHI3L2) as markers, produced IL-10 and IFNγ, suppressed CD4+ and CD8+ T cell proliferation comparably to Foxp3+ Tregs, and were increased in more advanced disease. High CHI3L2 expression correlated with good response to anti-PD-1/PD-L1 therapy in patients with melanoma.
Contributed by Paula Hochman
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.
Author Info: (1) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (2) Istituto Nazionale Genetica Mole
Author Info: (1) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (2) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (3) Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. Flow Cytometry Core, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. (4) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (5) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (6) Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. (7) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (8) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (9) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (10) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (11) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (12) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (13) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (14) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (15) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (16) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (17) Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. (18) Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. (19) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (20) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (21) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (22) Division of Hematopathology, European Institute of Oncology (IEO) IRCCS, Milan, Italy. (23) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (24) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (25) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (26) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (27) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (28) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. Department of Oncology and Hemato-Oncology, Universit degli Studi di Milano, Milan, Italy. (29) Pathology and Cytogenetics Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy. (30) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. Department of Oncology and Hemato-Oncology, Universit degli Studi di Milano, Milan, Italy. (31) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. (32) Faculty of Medicine and Surgery Vita-Salute San Raffaele University, Milan, Italy. Division of Thoracic Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy. (33) Division of Thoracic Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy. (34) Division of Thoracic Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy. (35) Department of Surgery, Milano-Bicocca University, San Gerardo Hospital, Monza, Italy. (36) Department of Pathology, San Gerardo Hospital, Monza, Italy. (37) Unit Operativa Chirurgia Epatobiliopancreatica e Digestiva, Ospedale San Paolo, Milan, Italy. Department of Health Sciences, Universit degli Studi di Milano, Milan, Italy. (38) Unit Operativa Chirurgia Epatobiliopancreatica e Digestiva, Ospedale San Paolo, Milan, Italy. (39) Unit Operativa Chirurgia Epatobiliopancreatica e Digestiva, Ospedale San Paolo, Milan, Italy. (40) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. Department of Biosciences, University of Milan, Milan, Italy. (41) Department of Transfusion Medicine and Hematology, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. (42) Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia-IRCCS, Turin, Italy. Department of Oncology, University of Torino, Turin, Italy. (43) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. geginat@ingm.org. Department of Clinical Sciences and Community Health, Universit degli Studi, Milan, Italy. geginat@ingm.org. (44) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. lanzavecchia@ingm.org. (45) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. abrignani@ingm.org. Department of Clinical Sciences and Community Health, Universit degli Studi, Milan, Italy. abrignani@ingm.org. (46) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. massimiliano.pagani@ifom.eu. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. massimiliano.pagani@ifom.eu. Department of Medical Biotechnology and Translational Medicine, Universit degli Studi, Milan, Italy. massimiliano.pagani@ifom.eu.
