Multimodal single-cell profiling of intrahepatic cholangiocarcinoma defines hyperactivated Tregs as a potential therapeutic target
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- Alvisi Giorgia
- 作成者
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- Federica Portale
- 作成者
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- Roberta Carriero
- 作成者
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- Karolina Pilipow
- 作成者
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- Guido Costa
- 作成者
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- Michela Polidoro
- 作成者
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- Ines Malenica
- 作成者
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- Simone Puccio
- 作成者
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- Lise Veronica
- 作成者
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- Zanon Veronica
- 作成者
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- Tufano Michele
- 作成者
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- Alessio Aghemo
- 作成者
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- Di Tommaso Luca
- 作成者
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- Peano Clelia
- 作成者
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- Cibella Javier
- 作成者
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- Iannacone Matteo
- 作成者
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- Manzo Teresa
- 作成者
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- Donadon Matteo
- 作成者
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- Torzilli Guido
- 作成者
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- Di Mitri Diletta
- 作成者
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- Lugli Enrico
- 作成者
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- Lleo Ana
- 作成者
メタデータ
- 公開日
- 2022-11-17
- 公開者
- Zenodo
- データ作成者 (e-Rad)
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- Alvisi Giorgia
- Termanini Alberto
- Soldani Cristiana
- Federica Portale
- Roberta Carriero
- Karolina Pilipow
- Guido Costa
- Michela Polidoro
- Barbara Franceschini
- Ines Malenica
- Simone Puccio
- Lise Veronica
- Galletti Giovanni
- Zanon Veronica
- Colombo Federico Simone
- De Simone Gabriele
- Tufano Michele
- Alessio Aghemo
- Di Tommaso Luca
- Peano Clelia
- Cibella Javier
- Iannacone Matteo
- Roychoudhuri Rahul
- Manzo Teresa
- Donadon Matteo
- Torzilli Guido
- Kunderfranco Paolo
- Di Mitri Diletta
- Lugli Enrico
- Lleo Ana
説明
Multimodal single-cell profiling of intrahepatic cholangiocarcinoma defines hyperactivated Tregs as a potential therapeutic target Abstract Background & aims: The landscape and function of the immune infiltrate of intrahepatic cholangiocarcinoma (iCCA), a rare, yet aggressive tumor of the biliary tract, remains poorly characterized, limiting development of successful immunotherapies. Herein, we aimed to define the molecular characteristics of tumor-infiltrating leukocytes with a special focus on CD4+ regulatory T cells (Tregs). Methods: We used high-dimensional single-cell technologies to characterize the T-cell and myeloid compartments of iCCA tissues, comparing these with their tumor-free peritumoral and circulating counterparts. We further used genomics and cellular assays to define the iCCA-specific role of a novel transcription factor, mesenchyme homeobox 1 (MEOX1), in Treg biology. Results: We found poor infiltration of putative tumor-specific CD39+ CD8+ T cells accompanied by abundant infiltration of hyperactivated CD4+ Tregs. Single-cell RNA-sequencing identified an altered network of transcription factors in iCCA-infiltrating compared to peritumoral T cells, suggesting reduced effector functions by tumor-infiltrating CD8+ T cells and enhanced immunosuppression by CD4+ Tregs. Specifically, we found that expression of MEOX1 was highly enriched in tumor-infiltrating Tregs, and demonstrated that MEOX1 overexpression is sufficient to reprogram circulating Tregs to acquire the transcriptional and epigenetic landscape of tumor-infiltrating Tregs. Accordingly, enrichment of the MEOX1-dependent gene program in Tregs was strongly associated with poor prognosis in a large cohort of patients with iCCA. Conclusions: We observed abundant infiltration of hyperactivated CD4+ Tregs in iCCA tumors along with reduced CD8+ T-cell effector functions. Interfering with hyperactivated Tregs should be explored as an approach to enhance antitumor immunity in iCCA. Lay summary: Immune cells have the potential to slow or halt the progression of tumors. However, some tumors, such as intrahepatic cholangiocarcinoma, are associated with very limited immune responses (and infiltration of cancer-targeting immune cells). Herein, we show that a specific population of regulatory T cells (a type of immune cell that actually suppresses the immune response) are hyperactivated in intrahepatic cholangiocarcinoma. Targeting these cells could enable cancer-targeting immune cells to act more effectively and should be looked at as a potential therapeutic approach to this aggressive cancer type.