生物
癌症研究
转录因子
转录组
肿瘤微环境
免疫系统
调节性T细胞
免疫学
T细胞
基因
基因表达
遗传学
白细胞介素2受体
作者
Feng Shan,Anthony R. Cillo,Carly Cardello,Daniel Y. Yuan,Sheryl Kunning,Jian Cui,Caleb Lampenfeld,Amanda L. Williams,Alexandra P. McDonough,Arjun Pennathur,James D. Luketich,John M. Kirkwood,Robert L. Ferris,Tullia C. Bruno,Creg J. Workman,Panayiotis V. Benos,Dario A.A. Vignali
出处
期刊:Science immunology
[American Association for the Advancement of Science (AAAS)]
日期:2023-09-29
卷期号:8 (87)
被引量:5
标识
DOI:10.1126/sciimmunol.adf6717
摘要
Human regulatory T cells (Tregs) are crucial regulators of tissue repair, autoimmune diseases, and cancer. However, it is challenging to inhibit the suppressive function of Tregs for cancer therapy without affecting immune homeostasis. Identifying pathways that may distinguish tumor-restricted Tregs is important, yet the transcriptional programs that control intratumoral Treg gene expression, and that are distinct from Tregs in healthy tissues, remain largely unknown. We profiled single-cell transcriptomes of CD4+ T cells in tumors and peripheral blood from patients with head and neck squamous cell carcinomas (HNSCC) and those in nontumor tonsil tissues and peripheral blood from healthy donors. We identified a subpopulation of activated Tregs expressing multiple tumor necrosis factor receptor (TNFR) genes (TNFR+ Tregs) that is highly enriched in the tumor microenvironment (TME) compared with nontumor tissue and the periphery. TNFR+ Tregs are associated with worse prognosis in HNSCC and across multiple solid tumor types. Mechanistically, the transcription factor BATF is a central component of a gene regulatory network that governs key aspects of TNFR+ Tregs. CRISPR-Cas9-mediated BATF knockout in human activated Tregs in conjunction with bulk RNA sequencing, immunophenotyping, and in vitro functional assays corroborated the central role of BATF in limiting excessive activation and promoting the survival of human activated Tregs. Last, we identified a suite of surface molecules reflective of the BATF-driven transcriptional network on intratumoral Tregs in patients with HNSCC. These findings uncover a primary transcriptional regulator of highly suppressive intratumoral Tregs, highlighting potential opportunities for therapeutic intervention in cancer without affecting immune homeostasis.
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