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Series GSE89477 Query DataSets for GSE89477
Status Public on Nov 26, 2017
Title Single-cell profiling of tumor infiltrating T cells
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Immune checkpoint blockade has shown tremendous anti-tumor potential in the clinic. However, these therapies are only effective in a subset of patients, so identification of additional immunomodulatory molecules that enhance the anti-tumor activity of these treatments may expand their clinical utility. In particular, identifying small molecules that complement existing immunotherapies has been relatively unexplored, so we performed a small molecule screen to identify compounds that can enhance co-inhibitory molecule blockade, to improve the anti-tumor adaptive immune response. Our unbiased screen identified inhibitors of cyclin-dependent kinase 4 and 6 (CDK4/6), including the FDA-approved palbociclib, as a class of small molecule compounds that exhibited significant immunostimulatory activity in vitro. In accordance with our in vitro finding of enhanced NFAT signaling, single-cell RNA-sequencing confirmed that in vivo exposure to CDK4/6 inhibitors enhanced NFAT signaling in tumor infiltrating T cells. Moreover, our results revealed that CDK4/6 inhibition up-regulated activation molecules and down-regulated suppressive molecules in these cells. CDK4/6 inhibition also increased the number of T cells with activated TCR (T cell receptor) signaling, as well as factors that are important for signal transduction downstream of TCR signaling. In summary, the impact of CDK4/6i on cell cycle progression and T cell proliferation are balanced favorably towards increased T cell recruitment and enhanced effector cell function, mediated in part by activation of the NFAT family of transcription factors. Further, our results demonstrate that CDK4/6i enhances PD-1 blockade through increased T-cell effector function and inhibition of immune suppressive cytokine production. While prolonged CDK4/6i treatment could be immunosuppressive due to adverse effects on lymphocyte proliferation, properly timed/sequenced CDK4/6i may potentiate the clinical impact of anti-PD-1/PD-L1 antibodies. As palbociclib is FDA-approved and multiple other CDK4/6 inhibitors are in clinical trials, we expect that this hypothesis will undergo rapid testing in humans.
Overall design Single-cell comparison of control and CDK4/6 inhibitor treated tumor infiltrating T cells
Contributor(s) Dries R, Deng J
Citation(s) 29101163
Submission date Nov 03, 2016
Last update date May 15, 2019
Contact name Ruben Dries
Organization name DFCI
Department Computational Biology
Lab Longwood Center
Street address 360 Longwood Ave
City Boston
ZIP/Postal code 02215
Country USA
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (384)
GSM2373111 A01_plate1_1
GSM2373112 A02_plate1_9
GSM2373113 A03_plate1_17
BioProject PRJNA352336
SRA SRP092523

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SOFT formatted family file(s) SOFTHelp
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Supplementary file Size Download File type/resource
GSE89477_information_raw_data.xlsx 37.6 Kb (ftp)(http) XLSX
GSE89477_log_normalized_expr_plus1.txt.gz 25.2 Mb (ftp)(http) TXT
GSE89477_phenodata_samples.txt.gz 1.0 Kb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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