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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Nov 18, 2021 |
| Title |
Cyclophosphamide enhances the anti-tumor potency of GITR engagement by increasing oligoclonal cytotoxic T cell fitness |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Immune checkpoint blockade (ICB) therapy is a standard treatment option for many malignancies, but it is only effective in a subset of patients. Combination strategies to overcome resistance are promising areas of investigation. Targeting glucocorticoidinduced TNFR-related (GITR) protein with agonist antibodies has shown efficacy in preclinical models, but GITR engagement does not control growth of advanced poorly immunogenic murine tumors such as B16 melanoma and has not yielded benefit in clinical trials. The alkylating agent cyclophosphamide (CTX) preferentially depletes regulatory T cells (Tregs) and expands tumor-specific effector T cells (Teffs) via homeostatic proliferation. Additionally, CTX directly induces tumor cell death, thereby releasing antigen to prime Teffs in a lymphopenic environment where there are fewer Tregs. GITR agonism has a net inhibitory effect on Tregs and yet activates Teff. We therefore hypothesized that CTX treatment prior to GITR agonism would promote potent anti-tumor immunity. Here we show that the combination of CTX and GITR agonism robustly controls tumor growth in several clinically relevant mouse models. Mechanistically, we show that the combination therapy causes tumor cell death, clonal expansion of highly active and terminally differentiated CD8+ T cells, and depletion of regulatory T cells by AICD. Control of tumor growth was also associated with the presence of an expanded population of highly activated tumor-infiltrating oligoclonal CD8+ T cells that lead to a global contracted TCR repertoire. Our studies show that the combination of CTX and GITR agonism is a rational chemo-immunotherapeutic approach that warrants further clinical investigation.
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| Overall design |
Single cell transcriptome and hashtaging and next geration TCR sequencing of 5 mice per condition
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| Contributor(s) |
Hirschhorn D, Mangarin L, Chow A, Merghoub T |
| Citation(s) |
34676831 |
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| Submission date |
Aug 17, 2021 |
| Last update date |
Nov 19, 2021 |
| Contact name |
Bic MSKCC |
| Organization name |
Memorial SLoan-Kettering Cancer Center
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| Street address |
1275 York Ave.
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10021 |
| Country |
USA |
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| Platforms (3) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (12)
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| GSM5526255 |
IgG_rep1,rep2,rep3,rep4,rep5 |
| GSM5526256 |
DTA_rep1,rep2,rep3,rep4,rep5 |
| GSM5526257 |
CTX_rep1,rep2,rep3,rep4,rep5 |
| GSM5526258 |
CTXDTA_rep1,rep2,rep3,rep4,rep5 |
| GSM5526259 |
IgG_HTO_rep1,rep2,rep3,rep4,rep5 |
| GSM5526260 |
DTA_HTO_rep1,rep2,rep3,rep4,rep5 |
| GSM5526261 |
CTX_HTO_rep1,rep2,rep3,rep4,rep5 |
| GSM5526262 |
CTXDTA_HTO_rep1,rep2,rep3,rep4,rep5 |
| GSM5526263 |
IgG_VDJ_rep1,rep2,rep3,rep4,rep5 |
| GSM5526264 |
DTA_VDJ_rep1,rep2,rep3,rep4,rep5 |
| GSM5526265 |
CTX_VDJ_rep1,rep2,rep3,rep4,rep5 |
| GSM5526266 |
CTXDTA_VDJ_rep1,rep2,rep3,rep4,rep5 |
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| Relations |
| BioProject |
PRJNA755702 |
| SRA |
SRP332921 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE182292_Hirschhorn_Gene_counts.csv.gz |
37.2 Mb |
(ftp)(http) |
CSV |
| GSE182292_Hirschhorn_annotations.txt.gz |
500.2 Kb |
(ftp)(http) |
TXT |
| GSE182292_RAW.tar |
2.8 Mb |
(http)(custom) |
TAR (of CSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
| Processed data provided as supplementary file |
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