NCBI Logo
GEO Logo
   NCBI > GEO > Accession DisplayHelp Not logged in | LoginHelp
GEO help: Mouse over screen elements for information.
          Go
Series GSE259409 Query DataSets for GSE259409
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
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.
 
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.
 
Contributor(s) Bai Z, Feng B, Tang L
Citation(s) 39322665
Submission date Feb 27, 2024
Last update date Nov 22, 2024
Contact name Rong Fan
E-mail(s) rong.fan@yale.edu
Organization name Yale University
Department Biomedical Engineering
Street address 55 Prospect St.
City New Haven
State/province Connecticut
ZIP/Postal code 06511
Country USA
 
Platforms (2)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (6)
GSM8115756 In_vivo_scRNA_seq_Fc_IL4
GSM8115757 In_vivo_scRNA_seq_PBS
GSM8115758 In_vitro_Multiome_Gene_IL4
Relations
BioProject PRJNA1081439

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

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 SelectorHelp
Raw data are available in SRA

| NLM | NIH | GEO Help | Disclaimer | Accessibility |
NCBI Home NCBI Search NCBI SiteMap