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| Status |
Public on May 31, 2024 |
| Title |
A type 2 cytokine Fc–IL-4 revitalizes 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 immunotherapies inducing type 1 immunity-centric anti-tumor responses have achieved dramatic clinical success but seldom led to long-term remission in part due to T cell exhaustion associated dysfunction. It remains unknown whether and how type 2 immunity can be orchestrated with type 1 immunity-based therapies to achieve long-lasting responses. Here, we show that an interleukin-4 fusion protein (Fc–IL-4), a type 2 cytokine, directly acts on terminally exhausted CD8+ T (CD8+ TTE) cells and specifically enhances their effector function and survival. Strikingly, Fc–IL-4 significantly augmented anti-tumor efficacy and induced durable cures in multiple solid tumor models when combined with type 1 immunity-based adoptive T cell transfer (ACT) and immune checkpoint blockade (ICB) therapies. Further, we found that Fc–IL-4 enhances the glycolysis and nicotinamide adenine dinucleotide (NAD+) level of the CD8+ TTE cells in a lactate dehydrogenase A (LDHA)-dependent manner, and the metabolic modulation is indispensable for the invigoration of the intratumoral CD8+ TTE cells and therefore the enhanced therapeutic efficacy mediated by Fc–IL-4. These findings suggest that Fc–IL-4 is a safe and effective type 2 cytokine-based immunotherapy that synergizes with type 1 immunity to potently induce long-term responses against cancer. Our work provides insight into the synergy between the two types of immune responses for cancer treatment and unveils an innovative strategy of incorporating type 2 immune factors for the design of next-generation cancer immunotherapy.
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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 missing |
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| Submission date |
Feb 27, 2024 |
| Last update date |
May 31, 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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