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.
Publication types
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Observational Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / immunology*
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Carcinoma, Non-Small-Cell Lung / secondary
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Carcinoma, Non-Small-Cell Lung / therapy
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Proliferation / genetics
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Chemotherapy, Adjuvant / methods
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Chitinases / metabolism
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Clonal Hematopoiesis / immunology*
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Colectomy
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Colon / pathology
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Colon / surgery
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / immunology*
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Colorectal Neoplasms / pathology
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Colorectal Neoplasms / therapy
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Datasets as Topic
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Disease Progression
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Drug Resistance, Neoplasm / immunology
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Female
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Flow Cytometry
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Forkhead Transcription Factors / metabolism
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Gene Expression Regulation, Neoplastic / immunology
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Granzymes / metabolism
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Humans
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Immune Checkpoint Inhibitors / pharmacology
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Immune Checkpoint Inhibitors / therapeutic use
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Kaplan-Meier Estimate
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Lung Neoplasms / genetics
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Lung Neoplasms / immunology*
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Lung Neoplasms / pathology
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Lung Neoplasms / therapy
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Male
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Middle Aged
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Primary Cell Culture
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Programmed Cell Death 1 Receptor / antagonists & inhibitors
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RNA-Seq
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Single-Cell Analysis
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T-Box Domain Proteins / metabolism
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
Substances
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EOMES protein, human
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FOXP3 protein, human
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Forkhead Transcription Factors
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Immune Checkpoint Inhibitors
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
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T-Box Domain Proteins
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CHI3L2 protein, human
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Chitinases
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GZMK protein, human
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Granzymes