title: Small cell lung cancer tumour cells induce regulatory T lymphocytes, and patient survival correlates negatively with FOXP3+ cells in tumour infiltrate.
abstract: 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.
authors.affiliation: Department of Respiratory Medicine and Allergy, King's College London, London, United Kingdom.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Philip
authors.initials: P
authors.lastname: Hodkinson
authors.forename: Fiona
authors.initials: F
authors.lastname: McLaren
authors.forename: Alison
authors.initials: A
authors.lastname: MacKinnon
authors.forename: William
authors.initials: W
authors.lastname: Wallace
authors.forename: Sarah
authors.initials: S
authors.lastname: Howie
authors.forename: Tariq
authors.initials: T
authors.lastname: Sethi
mesh_terms: D018288:Carcinoma, Small Cell / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006801:Humans; D016753:Interleukin-10 / Q000502:physiology; D019409:Interleukin-15 / Q000502:physiology; D008175:Lung Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D008213:Lymphocyte Activation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D019409:Interleukin-15; D016212:Transforming Growth Factor beta; D016753:Interleukin-10