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Series GSE179936 Query DataSets for GSE179936
Status Public on Oct 06, 2021
Title Single Cell RNA Sequencing reveals heterogenous tumor associated immune cell compartment in lean vs obese mice using an MC38 tumor model
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Immunotherapy is life saving for some cancer patients and while obesity can promote cancer, it may also increase immunotherapy efficacy.  Mechanisms of this effect have been unclear, although obesity can promote an inflammatory state that may modify tumor infiltrating lymphocytes and tumor associated macrophage (TAM) populations in tumors.  To identify mechanisms by which obesity affects anti-tumor immunity, diet-induced obese and lean C57BL/6 mice received subcutaneous murine MC38-CEA1 colon cancer tumors. Obesity increased tumor growth rate and tumor burden. Fewer immune cells were present in tumors from obese mice, and the T cells had an activated and exhausted phenotype. Macrophages in obese animals had decreased expression of iNOS2 and MHCII, supporting a weaker “M1” anti-tumor phenotype compared to lean mice. When treated with anti-PD-1 antibodies, however, obese mice had a greater absolute decrease in tumor burden than lean mice. PD-1 blockade repolarized the macrophages to an M1-phentoype in obese mice, but this did not occur in the lean mice. Mechanistically, leptin is a pro-inflammatory adipokine that is increased in obesity and may mediate enhanced anti-tumor immunity in obesity.  To test the effect of leptin on tumor growth and anti-tumor immunity, lean mice were treated with leptin and tumors were observed over time. Leptin had single-agent preventative and therapeutic anti-tumor efficacy similar to PD-1 checkpoint therapy.  These data demonstrate that obesity has dual effects in cancer through promotion of tumor cell initiation while also enhancing anti-tumor immunity through elevated levels of leptin that can reprogram inflammatory macrophages. 
 
Overall design 8-week-old C57BL/6 male mice were fed ad libitum a 10% kcal from fat (low fat) diet or a 45% kcal fat (high fat) diet (Research Diets D12450H and D12451, respectively). Following 28 weeks of diet treatment mice were injected subcutaneously with 2x10^5 MC38 cells. Tumors were collected on Day 20 post injection and mechanically and enzymatically digested using miltenyi mouse tumor digestion kit following manufacturer’s instructions. CD45+ cells were separated from tumor suspensions using CD45+ microbeads (miltenyi) and enriched for live cells using a dead cell removal kit (miltenyi). Three samples from each diet treatment group were resuspended in PBS + 0.4% FBS and pooled together in equal number of live cells prior to submitting to single cell sequencing.
 
Contributor(s) Bader J, Ye X, Rathmell J
Citation(s) 34772698
Submission date Jul 12, 2021
Last update date Jan 05, 2022
Contact name John Karijolich
E-mail(s) john.karijolich@vumc.org
Organization name Vanderbilt University Medical Center
Department PMI
Lab John Karijolich Lab
Street address 1211 Medical Center Drive
City Nashville
State/province TN
ZIP/Postal code 37232
Country USA
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (2)
GSM5437375 MC38_tumor_LFD
GSM5437376 MC38_tumor_HFD
Relations
BioProject PRJNA745944
SRA SRP327972

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Supplementary file Size Download File type/resource
GSE179936_LFD_samples.h5ad.gz 1.3 Gb (ftp)(http) H5AD
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Raw data are available in SRA
Processed data are available on Series record

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