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| Status |
Public on Jan 11, 2024 |
| Title |
Acquisition of suppressive function by CD4+ conventional T cells limits anti-tumor immunity driven by Treg depletion [RNA-seq II] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Regulatory T (Treg) cells are essential for immune homeostasis but inhibit immune rejection of cancer. Strategies to disrupt Treg-mediated cancer immunosuppression have been met with limited clinical success, but the underlying mechanisms for this failure are poorly understood. By modeling Treg-targeted immunotherapy in mice, we find that a subset of CD4+ Foxp3- conventional T (Tconv) cells with potent suppressive function undergoes activation and expansion upon depletion of Foxp3+ Treg cells and limits therapeutic efficacy. We noted that Foxp3- Tconv cells within tumors adopt a Treg-like transcriptional profile upon Treg depletion and acquire suppressive function. This is attributable to a Th2-like subset of CD4+ Tconv cells marked by expression of (C-C motif) receptor 8 (CCR8) and enriched in Treg-associated transcripts. CCR8+ Tconv cells are found in mouse and human tumors. Upon Treg depletion, CCR8+ Tconv cells undergo systemic and intratumoral activation and expansion, resulting in IL-10 dependent suppression of anti-tumor immunity. Consequently, conditional deletion of Il10 within T cells augments anti-tumor efficacy upon Treg-depletion in mice, and antibody blockade of IL-10 signaling synergizes with Treg depletion to overcome treatment resistance. These findings reveal a secondary layer of immunosuppression by Tconv cells released upon therapeutic Treg depletion and suggest that broader consideration of suppressive function within the T cell lineage is required for development of effective Treg-targeted therapies.
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| Overall design |
Syngeneic B16-F10 melanoma cells were subcutaneously implanted into Foxp3EGFP-DTR mice and ablated Treg cells through administration of DTx. T cells were isolated by FACS and subjected to RNA-Seq analysis
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| Contributor(s) |
Whiteside SK, Grant FM, Clarke JC, Evans AC, Roychoudhuri R |
| Citation(s) |
38100544 |
| |
| Submission date |
Jul 12, 2023 |
| Last update date |
Jan 11, 2024 |
| Contact name |
Rahul Roychoudhuri |
| E-mail(s) |
rr257@cam.ac.uk
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| Organization name |
University of Cambridge
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| Department |
Department of Pathology
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| Lab |
Roychoudhuri Laboratory
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| Street address |
Tennis Court Road
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| City |
Cambridge |
| ZIP/Postal code |
CB2 1QP |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (13)
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| This SubSeries is part of SuperSeries: |
| GSE236825 |
Acquisition of suppressive function by CD4+ conventional T cells limits anti-tumor immunity driven by Treg depletion. |
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| Relations |
| BioProject |
PRJNA994054 |
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