Highly prevalent colorectal cancer-infiltrating LAP⁺ Foxp3⁻ T cells exhibit more potent immunosuppressive activity than Foxp3⁺ regulatory T cells

Mucosal Immunol. 2014 Mar;7(2):428-39. doi: 10.1038/mi.2013.62. Epub 2013 Sep 25.


Although elevated CD4⁺Foxp3⁺ regulatory T cell (Treg) frequencies within tumors are well documented, the functional and phenotypic characteristics of CD4⁺Foxp3⁺ and CD4⁺Foxp3⁻ T cell subsets from matched blood, healthy colon, and colorectal cancer require in-depth investigation. Flow cytometry revealed that the majority of intratumoral CD4⁺Foxp3⁺ T cells (Tregs) were Helios⁺ and expressed higher levels of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and CD39 than Tregs from colon and blood. Moreover, ∼30% of intratumoral CD4⁺Foxp3⁻ T cells expressed markers associated with regulatory functions, including latency-associated peptide (LAP), lymphocyte activation gene-3 (LAG-3), and CD25. This unique population of cells produced interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), and was ∼50-fold more suppressive than Foxp3⁺ Tregs. Thus, intratumoral Tregs are diverse, posing multiple obstacles to immunotherapeutic intervention in colorectal malignancies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD / metabolism
  • Colorectal Neoplasms / immunology*
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Female
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Immunophenotyping
  • Inducible T-Cell Co-Stimulator Protein / metabolism
  • Integrin alpha Chains / metabolism
  • Interleukin-10 / biosynthesis
  • Lymphocyte Activation Gene 3 Protein
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Phenotype
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • Transforming Growth Factor beta / biosynthesis


  • Antigens, CD
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Inducible T-Cell Co-Stimulator Protein
  • Integrin alpha Chains
  • Transforming Growth Factor beta
  • alpha E integrins
  • Interleukin-10
  • Lymphocyte Activation Gene 3 Protein
  • Lag3 protein, human