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

<jats:title>Abstract</jats:title><jats:p>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<jats:sup>+</jats:sup> T lymphocytes coordinate and regulate immunity, a better understanding of interactions between SCLC tumour cells and CD4<jats:sup>+</jats:sup> 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 <jats:italic>de novo</jats:italic> differentiation of functional CD4<jats:sup>+</jats:sup>CD25<jats:sup>+</jats:sup>FOXP3<jats:sup>+</jats:sup>CD127<jats:sup>lo</jats:sup>Helios<jats:sup>−</jats:sup> regulatory T (Treg) cells in healthy blood lymphocytes. FOXP3<jats:sup>+</jats:sup> T cells were found in SCLC tumour biopsies, and patients with higher ratios of FOXP3<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup> T‐cell proliferation and was present in SCLC biopsy tumour cells. These novel findings demonstrate that SCLC tumour cells can induce CD4<jats:sup>+</jats:sup> 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.</jats:p>