Forkhead box P3 regulatory T cells coexisting with cancer associated fibroblasts are correlated with a poor outcome in lung adenocarcinoma

Recently, an association between tumor infiltrating Forkhead box P3 regulatory T cells (T reg ) and an unfavorable prognosis has been clinically shown in some cancers, but the mechanism of T reg induction in the tumor microenvironment remains uncertain. The aims of the present study were to examine the relationship between T reg and patient outcome and to investigate whether T reg induction is influenced by the characteristics of cancer‐associated fibroblasts (CAF) in lung adenocarcinoma. The numbers of T reg in both the tumor stroma and the tumor nest were counted in 200 consecutive pathological stage I lung invasive adenocarcinoma specimens. To examine whether the characteristics of CAF influence T reg induction, we selected and cultured CAF from low T reg and high T reg adenocarcinoma. The number of T reg was much higher in the stroma than in the nest ( P  <   0.01). Patients with high T reg had a significantly poorer prognosis than those with low T reg (overall survival: P  =   0.03; recurrence‐free survival: P  =   0.02; 5‐year overall survival: 85.4% vs 93.0%). Compared with the CAF from low T reg adenocarcinoma, culture supernatant of the CAF from high T reg adenocarcinoma induced more T reg ( P  =   0.01). Also, CAF from high T reg adenocarcinoma expressed significantly higher mRNA levels of transforming growth factor‐β ( P  =   0.01) and vascular endothelial growth factor ( P  =   0.01), both of which are involved in T reg induction. Our studies suggest the possibility that CAF expressing immunoregulatory cytokines may induce T reg in the stroma, creating a tumor‐promoting microenvironment in lung adenocarcinoma that leads to a poor outcome.