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

Nat Immunol. 2021 Jun;22(6):735-745. doi: 10.1038/s41590-021-00930-4. Epub 2021 May 20.

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

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / immunology*
  • Carcinoma, Non-Small-Cell Lung / secondary
  • Carcinoma, Non-Small-Cell Lung / therapy
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Proliferation / genetics
  • Chemotherapy, Adjuvant / methods
  • Chitinases / metabolism
  • Clonal Hematopoiesis / immunology*
  • Colectomy
  • Colon / pathology
  • Colon / surgery
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology*
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / therapy
  • Datasets as Topic
  • Disease Progression
  • Drug Resistance, Neoplasm / immunology
  • Female
  • Flow Cytometry
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Neoplastic / immunology
  • Granzymes / metabolism
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Kaplan-Meier Estimate
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy
  • Male
  • Middle Aged
  • Primary Cell Culture
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • RNA-Seq
  • Single-Cell Analysis
  • T-Box Domain Proteins / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • EOMES protein, human
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Immune Checkpoint Inhibitors
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • T-Box Domain Proteins
  • CHI3L2 protein, human
  • Chitinases
  • GZMK protein, human
  • Granzymes