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| Status |
Public on Aug 03, 2023 |
| Title |
Integrated BATF transcriptional network regulates suppressive intratumoral regulatory T cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 impacting 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), in non-tumor tonsil tissues and in 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 non-tumor 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. Finally, 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 impacting immune homeostasis.
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| Overall design |
We leveraged single-cell RNA sequencing (scRNA-seq) technology to provide a detailed view on the heterogeneity of Tregs in the TME by profiling CD4+ T cells from tumors and peripheral blood mononuclear cells (PBMC) taken from patients with HNSCC, and comparing them to CD4+ T cells isolated from inflamed tonsil tissues from patients with tonsilitis, and from non-inflamed tonsil tissues from patients with sleep apnea and to healthy donor (HD) PBMC. To dissect the phenotypic and functional effects of BATF in human activated Tregs, we performed RNA-seq of BATF KO activated Tregs and scrambled controls from six cord blood samples.
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| Contributor(s) |
Shan F, Cillo AR, Cardello C, Pennathur A, Luketich JD, Kirkwood JM, Bruno TC, Vignali DA |
| Citation(s) |
37713508 |
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| Submission date |
Aug 01, 2023 |
| Last update date |
Nov 21, 2023 |
| Contact name |
Feng Shan |
| E-mail(s) |
[email protected]
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| Phone |
4126943757
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| Organization name |
University of Pittsburgh
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| Street address |
Ford Building, 5051 Centre Ave
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| City |
Pittsburgh |
| State/province |
Pennsylvania |
| ZIP/Postal code |
15213 |
| Country |
USA |
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| Platforms (1) |
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| Samples (37)
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| GSM7670883 |
Human Tregs, BATF KO, rep4 |
| GSM7670884 |
Human Tregs, BATF KO, rep5 |
| GSM7670885 |
Human Tregs, BATF KO, rep6 |
| GSM7670886 |
Human Tregs, scrambled ctrl, rep1 |
| GSM7670887 |
Human Tregs, scrambled ctrl, rep2 |
| GSM7670888 |
Human Tregs, scrambled ctrl, rep3 |
| GSM7670889 |
Human Tregs, scrambled ctrl, rep4 |
| GSM7670890 |
Human Tregs, scrambled ctrl, rep5 |
| GSM7670891 |
Human Tregs, scrambled ctrl, rep6 |
| GSM7670892 |
tonsil tissue-TS-CITEseq |
| GSM7670893 |
tonsil tissue-TS-GEX |
| GSM7670894 |
tonsil tissue-KD-GEX |
| GSM7670895 |
tonsil tissue-JA-CITEseq |
| GSM7670896 |
tonsil tissue-JA-GEX |
| GSM7670897 |
tonsil tissue-RC-GEX |
| GSM7670898 |
tonsil tissue-SE-GEX |
| GSM7670899 |
Mel_198_PBL |
| GSM7670900 |
Mel_198_TIL |
| GSM7670901 |
Mel_178953_PBL |
| GSM7670902 |
Mel_178953_TIL |
| GSM7670903 |
Mel_TP290_PBL |
| GSM7670904 |
Mel_TP290_TIL |
| GSM7670905 |
Mel_TPF115_PBL |
| GSM7670906 |
Mel_TPF115_TIL |
| GSM7670907 |
NSCLC1_PBMC |
| GSM7670908 |
NSCLC1_TIL |
| GSM7670909 |
NSCLC2_PBMC |
| GSM7670910 |
NSCLC2_TIL |
| GSM7670911 |
NSCLC3_CITEseq |
| GSM7670912 |
NSCLC3_PBMC_TIL_GEX |
| GSM7670913 |
NSCLC4_CITEseq |
| GSM7670914 |
NSCLC4_PBMC_TIL_GEX |
| GSM7670915 |
SCLC1_PBMC |
| GSM7670916 |
SCLC1_TIL |
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| Relations |
| BioProject |
PRJNA1000909 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE239750_RAW.tar |
320.1 Mb |
(http)(custom) |
TAR (of TAB, TAR) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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