Small cell lung cancer tumour cells induce regulatory T lymphocytes, and patient survival correlates negatively with FOXP3+ cells in tumour infiltrate

Int J Cancer. 2012 Sep 15;131(6):E928-37. doi: 10.1002/ijc.27613. Epub 2012 May 14.


Small cell lung cancer (SCLC) kills at least one person every 2 hr in the United Kingdom. Some patients do relatively well but most have rapidly progressive disease. There is no effective treatment and overall 2-year survival is less than 5%. Patients with SCLC have poorly understood local and systemic immune defects and can be immunocompromised. As CD4(+) T lymphocytes coordinate and regulate immunity, a better understanding of interactions between SCLC tumour cells and CD4(+) T cells may lead to effective molecular immunotherapy. We show that some, but not all, SCLC tumour cell lines secrete molecules that induce IL-10 secretion by and de novo differentiation of functional CD4(+)CD25(+)FOXP3(+)CD127(lo)Helios(-) regulatory T (Treg) cells in healthy blood lymphocytes. FOXP3(+) T cells were found in SCLC tumour biopsies, and patients with higher ratios of FOXP3(+) cells in tumour infiltrates have a worse survival rate. The inhibitory effect of SCLC tumour cells was not affected by blocking IL-10 receptor or TGF-β signalling but was partially reversed by blocking IL-15, which is reported to be involved in human Treg cells induction. IL-15 was secreted by SCLC cells that inhibited CD4(+) T-cell proliferation and was present in SCLC biopsy tumour cells. These novel findings demonstrate that SCLC tumour cells can induce CD4(+) T-cell-mediated immunosuppression. This gives a potential mechanism by which SCLC tumour cells may downregulate local and systemic immune responses and contribute to poor patient survival. Our data suggest that IL-15 and Treg cells are potential new therapeutic targets to improve immune response and patient survival in SCLC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Small Cell / immunology*
  • Carcinoma, Small Cell / mortality
  • Carcinoma, Small Cell / pathology
  • Cell Cycle
  • Cell Line, Tumor
  • Forkhead Transcription Factors / analysis*
  • Humans
  • Interleukin-10 / physiology
  • Interleukin-15 / physiology
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Lymphocyte Activation
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta / physiology


  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-15
  • Transforming Growth Factor beta
  • Interleukin-10