BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors
BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors
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DOI：
10.1126/sciimmunol.abk0957
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发表时间：
2022-10-01
影响因子：
24.8
通讯作者：
Nishikawa, Hiroyoshi
中科院分区：
文献类型：
--
作者：
Itahashi, Kota;Irie, Takuma;Nishikawa, Hiroyoshi
调节性 T (Treg) 细胞可抑制荷瘤宿主的有效抗肿瘤免疫，从而成为癌症免疫治疗的有希望的靶标。尽管 Treg 细胞在肿瘤免疫中很重要，但人们对其在肿瘤微环境 (TME) 中的分化过程和表观遗传特征知之甚少。在这里，我们发现，与 CD8+ T 细胞、TME 中的传统 CD4+ T 细胞和外周 Treg 细胞相比，人类肺癌 TME 中的 Treg 细胞具有完全不同的开放染色质谱。包括ATAC、单细胞RNA和单细胞ATAC测序在内的整合测序分析表明，BATF、IRF4、NF-KB和NR4A是TME中Treg细胞分化的重要转录因子。特别是，BATF 被认为是一个关键的调节因子，它通过表观遗传控制激活相关基因的表达来利用 Treg 细胞的分化，从而导致 TME 中 Treg 细胞的稳健性。单细胞测序方法还揭示，组织驻留和肿瘤浸润的 Treg 细胞遵循一条共同的分化和激活途径，以 BATF 依赖性方式走向组织和肿瘤中具有最高分化和激活表型的 Treg 细胞。 Treg 细胞中 BATF 缺乏显着抑制肿瘤生长，BATF 高表达与肺癌、肾癌和黑色素瘤的不良预后相关。这些发现表明TME中Treg细胞的特定染色质重塑和分化程序之一，可应用于Treg细胞靶向疗法的开发。
Regulatory T (Treg) cells suppress effective antitumor immunity in tumor-bearing hosts, thereby becoming promising targets in cancer immunotherapy. Despite the importance of Treg cells in tumor immunity, little is known about their differentiation process and epigenetic profiles in the tumor microenvironment (TME). Here, we showed that Treg cells in the TME of human lung cancers harbored a completely different open chro-matin profile compared with CD8+ T cells, conventional CD4+ T cells in the TME, and peripheral Treg cells. The integrative sequencing analyses including ATAC, single-cell RNA, and single-cell ATAC sequencing revealed that BATF, IRF4, NF-KB, and NR4A were important transcription factors for Treg cell differentiation in the TME. In par-ticular, BATF was identified as a key regulator, which leveraged Treg cell differentiation through epigenetically controlling activation-associated gene expression, resulting in the robustness of Treg cells in the TME. The single -cell sequencing approaches also revealed that tissue-resident and tumor-infiltrating Treg cells followed a common pathway for differentiation and activation in a BATF-dependent manner heading toward Treg cells with the most differentiated and activated phenotypes in tissues and tumors. BATF deficiency in Treg cells re-markably inhibited tumor growth, and high BATF expression was associated with poor prognosis in lung cancer, kidney cancer, and melanoma. These findings indicate one of the specific chromatin remodeling and differen-tiation programs of Treg cells in the TME, which can be applied in the development of Treg cell-targeted therapies.