Department of Otorhinolaryngology Head and Neck Surgery, the First Affiliated Hospital, Sun Yat-Sen University, 2nd Zhongshan Road 58#, Guangzhou, 510080, Guangdong, P.R. China.
Department of Allergy, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, P.R. China.
Head Face Med. 2024 Oct 26;20(1):62. doi: 10.1186/s13005-024-00466-6.
Activated regulatory T cells (aTregs) play a vital role in promoting a tumor immunosuppressive microenvironment in laryngeal squamous cell carcinoma (LSCC). However, the regulatory factors that induce the generation of aTregs are not clear. Herein, we investigated the effect of amphiregulin (AREG) on the production of aTregs in the tumor microenvironment of LSCC.
Immunohistochemical (IHC) analysis was conducted to examine the expression of AREG and FOXP3, and their association with clinical parameters and patient outcomes was demonstrated. The expression level of EGFRs in three functional subsets of Tregs was assessed, and the induction of CD4 T cells into aTregs in the presence or absence of AREG or Gefitinib was analyzed using flow cytometry.
Our results showed a higher expression level of AREG was significantly related to advanced clinical stage and worse survival, particularly with increased infiltration of Tregs in LSCC tumor tissue. The in vitro study showed that AREG significantly promoted the differentiation of aTregs, and enhanced the inhibitory effect of Tregs on T cell proliferation, which could be reversed by epidermal growth factor receptor (EGFR) inhibitors. In addition, we found that EGFR was highly expressed in aTregs, but not in other subsets of Tregs. It is suggested that AREG might induce aTregs, and enhance the immunosuppressive function of Tregs via the AREG/EGFR signal pathway.
Collectively, this study revealed the role and mechanism of AREG in negative immune regulation, and targeting AREG might be a novel immunotherapy for LSCC.
活化的调节性 T 细胞（aTregs）在促进喉鳞状细胞癌（LSCC）肿瘤免疫抑制微环境中起着至关重要的作用。然而，诱导 aTregs 产生的调节因子尚不清楚。在此，我们研究了 Amphiregulin（AREG）对 LSCC 肿瘤微环境中 aTregs 产生的影响。
通过免疫组织化学（IHC）分析检测 AREG 和 FOXP3 的表达，并证明其与临床参数和患者预后的关系。评估 EGFR 在 Treg 三个功能亚群中的表达水平，并通过流式细胞术分析在存在或不存在 AREG 或 Gefitinib 的情况下将 CD4 T 细胞诱导为 aTregs。
我们的结果表明，AREG 的高表达水平与晚期临床分期和较差的生存显著相关，特别是在 LSCC 肿瘤组织中 Treg 的浸润增加。体外研究表明，AREG 可显著促进 aTregs 的分化，并增强 Treg 对 T 细胞增殖的抑制作用，这种作用可被表皮生长因子受体（EGFR）抑制剂逆转。此外，我们发现 EGFR 在 aTregs 中高表达，但在其他 Treg 亚群中不表达。这表明 AREG 可能通过 AREG/EGFR 信号通路诱导 aTregs，并增强 Treg 的免疫抑制功能。
综上所述，本研究揭示了 AREG 在负性免疫调节中的作用和机制，靶向 AREG 可能为 LSCC 的一种新的免疫治疗方法。
