Clinical significance of expanded Foxp3(+) Helios(−) regulatory T cells in patients with non-small cell lung cancer

The functions of different regulatory T cell (T(reg)) types in cancer progression are unclear. Recently, expression of the transcription factor Helios was proposed as a marker for natural (non-induced) T(reg)s. The present study investigated the clinical significance of Helios expression in patients with non-small cell lung cancer (NSCLC). We enrolled 64 patients with NSCLC, of whom 45 were treated surgically and 19 received chemotherapy because of advanced/recurrent disease. Their peripheral blood mononuclear cells were examined by flow cytometry. From the 45 surgery patients, we matched 9 patients with recurrent disease with 9 stage-matched patients without recurrence (n=18), compared their specimens immunohistochemically for tumor infiltrating lymphocytes (TILs) and analyzed these data against clinicopathological factors. Helios expression in Foxp3(+) T(reg)s was 47.5±13.3% in peripheral blood and 18.1±13.4% in tumor specimens. Percentage of Helios(−) T(reg)s among CD4(+) T cells were significantly higher in the cancer patients (2.4%), especially those with stage IA disease (2.6%) than in healthy donors (1.5%; P<0.001). Patients with low levels of Helios expression in T(reg)s among their TILs had significantly poorer survival (P=0.038). Helios(−) T(reg)s may affect immune suppression, even in early stage NSCLC; they could also be a useful prognostic biomarker in patients with NSCLC, and possibly a novel cancer immunotherapy target.