Open AccessForkhead box P3 regulatory T cells coexisting with cancer associated fibroblasts are correlated with a poor outcome in lung adenocarcinoma
Author(s) -
Kinoshita Tomonari,
Ishii Genichiro,
Hiraoka Nobuyoshi,
Hirayama Shunki,
Yamauchi Chisako,
Aokage Keiju,
Hishida Tomoyuki,
Yoshida Junji,
Nagai Kanji,
Ochiai Atsushi
Publication year - 2013
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12099
Subject(s) - adenocarcinoma , stroma , medicine , tumor microenvironment , lung , cancer , transforming growth factor , oncology , cancer research , pathology , immunohistochemistry
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.