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GEO help: Mouse over screen elements for information. |
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Status |
Public on May 31, 2024 |
Title |
A type 2 cytokine Fc–IL-4 revitalises exhausted CD8+ T cells against cancer |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing Genome binding/occupancy profiling by high throughput sequencing
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Summary |
Current cancer immunotherapy predominately focuses on eliciting type 1 immune responses fighting cancer; however, long-term complete remission remains uncommon. A pivotal question arises whether type 2 immunity can be orchestrated alongside type 1-centric immunotherapy to achieve enduring response against cancer. Here, we show that an interleukin-4 fusion protein (Fc–IL-4), a typical type 2 cytokine, directly acts on CD8+ T cells and enriches functional terminally exhausted CD8+ T (CD8+ TTE) cells in the tumour. Consequently, Fc–IL-4 remarkably enhances anti-tumour efficacy of type 1 immunity-centric adoptive T cell transfer (ACT) or immune checkpoint blockade (ICB) therapies and induces durable remission across multiple syngeneic and xenograft tumour models. Mechanistically, we uncovered that Fc–IL-4 signals through both signal transducer and activator of transcription 6 (STAT6) and mammalian target of rapamycin (mTOR) pathways, augmenting the glycolytic metabolism and nicotinamide adenine dinucleotide (NAD+) level of CD8+ TTE cells in a lactate dehydrogenase A (LDHA)-dependent manner. The metabolic modulation mediated by Fc–IL-4 is indispensable for reinvigorating intratumoural CD8+ TTE cells. These findings underscore Fc–IL-4 as a potent type 2 cytokine-based immunotherapy that synergizes effectively with type 1 immunity to elicit long-lasting responses against cancer. Our study not only sheds light on the synergy between these two types of immune responses but also unveils an innovative strategy for advancing next-generation cancer immunotherapy by integrating type 2 immune factors.
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Overall design |
1. For the in vivo study, B16F10 tumor-bearing CD45.2+Thy1.2+ C57BL/6 mice received i.v. adoptive transfer of activated Thy1.1+ PMEL CD8+ T cells (5 × 106 per mouse), followed by four doses of peritumoral (p.t.) administration of Fc–IL-4 (20 μg per mouse) or PBS control every other day. After the above treatment, tumors were collected and digested, and tumor-infiltrating PMEL T cells were enriched and sorted out for scRNA-seq. 2. For the in vitro study, single-cell co-profiling of epigenomic landscape and gene expression in the same single nuclei was performed on the ex vivo-induced CD8+ terminally exhausted T cells in the presence or absence of 20ng/mL IL-4.
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Contributor(s) |
Bai Z, Feng B, Tang L |
Citation(s) |
39322665 |
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Submission date |
Feb 27, 2024 |
Last update date |
Nov 22, 2024 |
Contact name |
Rong Fan |
E-mail(s) |
rong.fan@yale.edu
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Organization name |
Yale University
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Department |
Biomedical Engineering
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Street address |
55 Prospect St.
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City |
New Haven |
State/province |
Connecticut |
ZIP/Postal code |
06511 |
Country |
USA |
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Platforms (2) |
GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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Samples (6)
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Relations |
BioProject |
PRJNA1081439 |
Supplementary file |
Size |
Download |
File type/resource |
GSE259409_RAW.tar |
129.1 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
GSE259409_atac_fragments.tsv.gz |
2.6 Gb |
(ftp)(http) |
TSV |
GSE259409_atac_fragments.tsv.gz.tbi.gz |
1.0 Mb |
(ftp)(http) |
TBI |
GSE259409_atac_peak_annotation.tsv.gz |
1.8 Mb |
(ftp)(http) |
TSV |
GSE259409_filtered_feature_bc_matrix.h5 |
214.4 Mb |
(ftp)(http) |
H5 |
SRA Run Selector |
Raw data are available in SRA |
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