National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433, China.
J Mol Med (Berl). 2014 May;92(5):539-50. doi: 10.1007/s00109-014-1143-4. Epub 2014 Mar 26.
Tumors can recruit, induce, and expand regulatory T cells (Tregs) to suppress antitumor immune responses for survival and progression. The complicated tumor-related Treg subsets and their functional mechanisms are not fully addressed yet. We have previously identified a novel CD4⁺CD69⁺Foxp3⁻ Treg subset in tumor-bearing mice, which suppresses CD4 T cell response via membrane-bound transforming growth factor beta 1 (mTGF-β1) and then promotes tumor progression. In hepatocellular carcinoma patients, here, we identified tumor-infiltrating human CD4⁺CD69⁺ Tregs which represent ~67.2 % of tumor-infiltrating CD4 T cells that is significantly higher than conventional CD4⁺CD25⁺Foxp3⁺ Tregs. They expressed mTGF-β1, PD-1, and CTLA-4, but not CD25 or Foxp3, and only produced a little interleukin (IL)-10 and TGF-β1. More importantly, they significantly suppressed CD4 T cell response via mTGF-β1 in vitro. Furthermore, the percentage of these CD4⁺CD69⁺ Tregs in tumor tissue was significantly correlated with tumor progression, which is more pronounced at the late stage of cancer patients. Thus, we have identified a tumor-induced new population of human CD4⁺CD69⁺ Tregs in cancer patients with phenotype of CD25⁻Foxp3⁻mTGF-β1⁺CTLA-4⁺PD-1⁺, and these Tregs can suppress antitumor immune response via mTGF-β1. Our results not only enrich the family of Treg subsets, providing new mechanistic insight to tumor-induced immune suppression in human, but also suggest a potential target for cancer immunotherapy.
CD4⁺CD69⁺Foxp3⁻ regulatory T cells were identified in hepatocellular carcinoma patients. These Treg cells inhibit T cell response via membrane-bound TGF-β. The percentage of these cells was significantly correlated with tumor progression. The percentage of these cells was higher than conventional CD4⁺CD25⁺Foxp3⁺ Tregs. These Treg cells not only exist in tumor-bearing mice, but also in cancer patients.
肿瘤可以招募、诱导和扩增调节性 T 细胞（Tregs），以抑制抗肿瘤免疫反应以实现生存和进展。复杂的肿瘤相关 Treg 亚群及其功能机制尚未完全阐明。我们之前在荷瘤小鼠中鉴定了一种新型的 CD4 ⁺ CD69 ⁺ Foxp3 ⁻ Treg 亚群，其通过膜结合转化生长因子β 1（mTGF-β1）抑制 CD4 T 细胞反应，然后促进肿瘤进展。在肝细胞癌患者中，我们在此鉴定了肿瘤浸润的人 CD4 ⁺ CD69 ⁺ Tregs，其代表肿瘤浸润性 CD4 T 细胞的约 67.2%，显著高于传统的 CD4 ⁺ CD25 ⁺ Foxp3 ⁺ Tregs。它们表达 mTGF-β1、PD-1 和 CTLA-4，但不表达 CD25 或 Foxp3，并且仅产生少量白细胞介素（IL）-10 和 TGF-β1。更重要的是，它们通过体外 mTGF-β1 显著抑制 CD4 T 细胞反应。此外，肿瘤组织中这些 CD4 ⁺ CD69 ⁺ Tregs 的百分比与肿瘤进展显著相关，在癌症患者的晚期更为明显。因此，我们在癌症患者中鉴定了一种肿瘤诱导的新型人 CD4 ⁺ CD69 ⁺ Treg 亚群，其表型为 CD25 ⁻ Foxp3 ⁻ mTGF-β1 ⁺ CTLA-4 ⁺ PD-1 ⁺，这些 Tregs 可通过 mTGF-β1 抑制抗肿瘤免疫反应。我们的研究结果不仅丰富了 Treg 亚群家族，为人类肿瘤诱导的免疫抑制提供了新的机制见解，而且还为癌症免疫治疗提供了一个潜在的靶点。
在肝细胞癌患者中鉴定出 CD4 ⁺ CD69 ⁺ Foxp3 ⁻ 调节性 T 细胞。这些 Treg 细胞通过膜结合 TGF-β 抑制 T 细胞反应。这些细胞的百分比与肿瘤进展显著相关。这些细胞的百分比高于传统的 CD4 ⁺ CD25 ⁺ Foxp3 ⁺ Tregs。这些 Treg 细胞不仅存在于荷瘤小鼠中，也存在于癌症患者中。
