|
| Status |
Public on Jun 20, 2024 |
| Title |
Transcriptomic studies on ruxolitinib with or without checkpoint inhibitors as a cancer therapy |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Other
|
| Summary |
Unleashing anti-tumor T cell activity by checkpoint inhibition is effective in many cancer patients but clinical response rates remain limited. Myeloid derived suppressor cells erode antitumor lymphocyte numbers and function, and correlate with resistance to checkpoint inhibitors. By screening small molecule libraries, we identified JAK inhibitors’ ability to rescue T cell function. Despite its documented immune suppressive properties, the prototypical JAK inhibitor ruxolitinib enhanced the efficacy of immune checkpoint blockade in cancer. This effect correlated with loss of suppressive gene expression, and acquisition of immunostimulatory molecular markers and T cell stimulatory activity in myeloid cells. In preclinical models, ruxolitinib significantly improved the function and increased the total numbers of activated tumor-infiltrating NK and CD4 T cells compared to checkpoint blockade alone and the efficacy was conditional on granulocytic cells. In addition to myeloid reprogramming in the tumor, ruxolitinib blunts G-CSF signaling in the bone marrow to prevent expression of suppressive and chemotaxis genes in neutrophils.
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| Overall design |
Immunocompetent mice bearing wt MC38, JAK1ko MC38, LLC1 or EL4 tumors were treated with ruxolitinib or vehicle (daily gavage) and anti-PD1 plus anti-CTLA4 (ICB), or isotype control (intraperitoneal injection every 7 d). Treatment was initiated once tumors became palpable. At a pre-selected timepoint tumors were harvested and processed into single-cell suspension. Live single CD45+ cells were sorted and subjected to CITE-seq using a standard protocol for 10X Genomics 3' single-cell transcriptome with antibody-derived protein barcoding. Bone marrow and blood CD45+ were harvested as single-cell suspensions and processed using the same CITE-seq protocol. To test the effect of ruxolitinib on splenocytes during persistent viral infection, mice infected with LCMV Clone 13 (2x10^6 pfu) were treated with ruxolitinib or vehicle by daily gavage from the day of infection and at 10 d post infection single-cell splenocyte suspension sorted by flow cytometry. Live single CD45+ splenocytes were subjected to the same CITE-seq protocol.
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| Web link |
https://www.science.org/doi/10.1126/science.ade8520
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| Contributor(s) |
Zak J, Pratumchai I, Teijaro JR |
| Citation(s) |
38900864 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 AI123210 |
Novel Strategies for Controlling Persistent Viral Infection |
THE SCRIPPS RESEARCH INSTITUTE |
John Ross Teijaro |
| UL1 TR002550 |
Scripps Translational Science Institute |
THE SCRIPPS RESEARCH INSTITUTE |
Eric Jeffrey Topol |
| R01 AI164744 |
The role of IL-27 in sustaining the exhausted CD8 T cell response to persistent infection and cancer. |
THE SCRIPPS RESEARCH INSTITUTE |
John Ross Teijaro |
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| |
| Submission date |
Jul 25, 2022 |
| Last update date |
Jun 21, 2024 |
| Contact name |
John R Teijaro |
| E-mail(s) |
teijaro@scripps.edu
|
| Organization name |
The Scripps Research Institute
|
| Department |
Immunology and Microbial Science
|
| Street address |
10550 North Torrey Pines Rd
|
| City |
San Diego |
| State/province |
CA |
| ZIP/Postal code |
92037 |
| Country |
USA |
| |
|
| Platforms (2) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
| GPL30172 |
NextSeq 2000 (Mus musculus) |
|
| Samples (14)
|
| GSM6381779 |
MC38_wt_BM_blood, ADT- and HTO-derived cDNA |
| GSM6381780 |
MC38_JAK1ko_TIC and LCMV_S, mRNA-derived cDNA |
| GSM6381781 |
MC38_JAK1ko_TIC and LCMV_S, ADT- and HTO-derived cDNA |
| GSM6381782 |
EL4_TIC, mRNA-derived cDNA |
| GSM6381783 |
EL4_TIC, ADT- and HTO-derived cDNA |
| GSM6381784 |
LLC1_TIC, mRNA-derived cDNA |
| GSM6381785 |
LLC1_TIC, ADT- and HTO-derived cDNA |
| GSM6381786 |
tumor-infiltrating NK cells, vehicle treated mice |
| GSM6381787 |
tumor-infiltrating NK cells, ICB treated mice |
| GSM6381788 |
tumor-infiltrating NK cells, ruxolitinib treated mice |
| GSM6381789 |
tumor-infiltrating NK cells, ICB and ruxolitinib treated mice |
|
| Relations |
| BioProject |
PRJNA861983 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE209647_EL4_TIC_barcodes.tsv.gz |
139.2 Kb |
(ftp)(http) |
TSV |
| GSE209647_EL4_TIC_features.tsv.gz |
284.3 Kb |
(ftp)(http) |
TSV |
| GSE209647_EL4_TIC_matrix.mtx.gz |
180.6 Mb |
(ftp)(http) |
MTX |
| GSE209647_LLC1_TIC_barcodes.tsv.gz |
153.6 Kb |
(ftp)(http) |
TSV |
| GSE209647_LLC1_TIC_features.tsv.gz |
284.3 Kb |
(ftp)(http) |
TSV |
| GSE209647_LLC1_TIC_matrix.mtx.gz |
182.3 Mb |
(ftp)(http) |
MTX |
| GSE209647_MC38_JAK1ko_TIC_and_LCMV_S_barcodes.tsv.gz |
145.8 Kb |
(ftp)(http) |
TSV |
| GSE209647_MC38_JAK1ko_TIC_and_LCMV_S_features.tsv.gz |
284.3 Kb |
(ftp)(http) |
TSV |
| GSE209647_MC38_JAK1ko_TIC_and_LCMV_S_matrix.mtx.gz |
263.7 Mb |
(ftp)(http) |
MTX |
| GSE209647_MC38_wt_BM_blood_barcodes.tsv.gz |
154.4 Kb |
(ftp)(http) |
TSV |
| GSE209647_MC38_wt_BM_blood_features.tsv.gz |
284.3 Kb |
(ftp)(http) |
TSV |
| GSE209647_MC38_wt_BM_blood_matrix.mtx.gz |
224.2 Mb |
(ftp)(http) |
MTX |
| GSE209647_MC38_wt_TIC_barcodes.tsv.gz |
125.8 Kb |
(ftp)(http) |
TSV |
| GSE209647_MC38_wt_TIC_features.tsv.gz |
284.3 Kb |
(ftp)(http) |
TSV |
| GSE209647_MC38_wt_TIC_matrix.mtx.gz |
189.0 Mb |
(ftp)(http) |
MTX |
| GSE209647_RAW.tar |
1.2 Mb |
(http)(custom) |
TAR (of TAB) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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