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

TY - JOUR

T1 - Small cell lung cancer tumour cells induce regulatory T lymphocytes, and patient survival correlates negatively with FOXP3+ cells in tumour infiltrate

AU - Wang, Wei

AU - Hodkinson, Philip

AU - McLaren, Fiona

AU - MacKinnon, Alison

AU - Wallace, William

AU - Howie, Sarah

AU - Sethi, Tariq

PY - 2012/9/15

Y1 - 2012/9/15

N2 - 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+CD127loHelios- 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-beta 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.

AB - 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+CD127loHelios- 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-beta 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.

KW - Carcinoma, Small Cell

KW - Cell Cycle

KW - Cell Line, Tumor

KW - Forkhead Transcription Factors

KW - Humans

KW - Interleukin-10

KW - Interleukin-15

KW - Lung Neoplasms

KW - Lymphocyte Activation

KW - T-Lymphocytes, Regulatory

KW - Transforming Growth Factor beta

U2 - 10.1002/ijc.27613

DO - 10.1002/ijc.27613

M3 - Article

C2 - 22532287

SN - 0020-7136

VL - 131

SP - E928-E937

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 6

ER -