Nakayama Shoko, Yokote Taiji, Akioka Toshikazu, Hiraoka Nobuya, Nishiwaki Uta, Miyoshi Takuji, Iwaki Kazuki, Takayama Ayami, Masuda Yuki, Hatooka Jun, Fujimoto Mayumi, Nishimura Yasuichiro, Tsuji Motomu
First Department of Internal Medicine.
Division of Mathematics, and.
Blood Adv. 2017 Mar 6;1(8):486-493. doi: 10.1182/bloodadvances.2016000885. eCollection 2017 Mar 14.
Regulatory T cells (Tregs) specifically express the transcription factor forkhead box P3 (FOXP3) and contribute to tumor progression. FOXP3-positive cells have been recently proven to be heterogeneous in phenotype and function, including effector Tregs (eTregs), naïve Tregs, and non-Tregs, which harbor no suppressive function. Therefore, it is crucial to investigate the "true Treg (eTreg)" population, rather than the entire FOXP3 population, with regards to their effect on tumor immunity. In particular, in diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), FOXP3-positive cells correlated with a better prognosis. The present study sought to evaluate the relationship between the prognosis of DLBCL, NOS patients and the infiltration of true Tregs by employing dual immunostaining with FOXP3 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). CTLA-4 is a negative immunomodulatory known to be expressed by eTregs, but not by non-Tregs. Lymph nodes from 82 nodal DLBCL, NOS patients were stained with anti-FOXP3 and anti-CTLA-4 antibodies. A high infiltration of FOXP3-positive cells was associated with a significantly better prognosis than patients with low levels of FOXP3-positive cells for overall survival (OS) ( = .0233). In sharp contrast, a high infiltration of FOXP3/CTLA-4 double-positive cells was significantly associated with a poor prognosis than patients with low levels of FOXP3/CTLA-4 double-positive cells for OS ( = .0121) and progression-free survival ( = .0171), independent of the international prognostic index. FOXP3/CTLA-4 double-positive cells, eTregs, play an important role in DLBCL, NOS progression.
调节性T细胞（Tregs）特异性表达转录因子叉头框蛋白P3（FOXP3）并促进肿瘤进展。最近已证实FOXP3阳性细胞在表型和功能上具有异质性，包括效应调节性T细胞（eTregs）、初始调节性T细胞和无抑制功能的非调节性T细胞。因此，研究“真正的调节性T细胞（eTregs）”群体而非整个FOXP3群体对肿瘤免疫的影响至关重要。特别是在未另行说明的弥漫性大B细胞淋巴瘤（DLBCL，NOS）中，FOXP3阳性细胞与较好的预后相关。本研究旨在通过采用FOXP3和细胞毒性T淋巴细胞相关抗原4（CTLA-4）双重免疫染色来评估DLBCL，NOS患者的预后与真正的调节性T细胞浸润之间的关系。CTLA-4是一种已知由eTregs表达而非非调节性T细胞表达的负性免疫调节因子。对82例淋巴结DLBCL，NOS患者的淋巴结进行抗FOXP3和抗CTLA-4抗体染色。对于总生存期（OS），FOXP3阳性细胞高浸润的患者比FOXP3阳性细胞水平低的患者预后明显更好（P = 0.0233）。与之形成鲜明对比的是，对于OS（P = 0.0121）和无进展生存期（P = 0.0171），FOXP3/CTLA-4双阳性细胞高浸润的患者比FOXP3/CTLA-4双阳性细胞水平低的患者预后明显更差，且与国际预后指数无关。FOXP3/CTLA-4双阳性细胞，即eTregs，在DLBCL，NOS进展中起重要作用。
