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.