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Series GSE249909 Query DataSets for GSE249909
Status Public on Mar 01, 2024
Title MCL1 inhibition targets Myeloid Derived Suppressors Cells, promotes antitumor immunity and enhances the efficacy of immune checkpoint blockade
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Immune checkpoint inhibitors (ICIs) are now the first line treatment for patients with advanced melanoma. Despite promising clinical results, many patients fail to respond to these therapies. BH3 mimetics, a novel class of small molecule inhibitors that bind and inhibit anti-apoptotic members of the BCL2 family proteins such as BCL2 or MCL1, have been very successful in treating hematologic malignancies. However, there are limited studies on the immunomodulatory role of the BH3 mimetics. Several factors contribute to ICI resistance including myeloid-derived suppressor cells (MDSCs) that exert immunosuppressive effects through direct and indirect inhibition of antitumor immunity. Thus, targeting MDSCs to enhance antitumor immunity has the potential to enhance the efficacy of ICIs. In this study, we show that the MCL1 inhibitor S64315 reduces melanoma tumor growth in an immune cell dependent manner in mice. Specifically, S64315 enhances antitumor immunity by reducing MDSC frequency and by promoting the activity of CD8+ T cells. Additionally, human MDSCs are 10 times more sensitive to S64315 than cutaneous melanoma lines. Further, we found that a higher expression of MCL1 is associated with poor survival for patients treated with anti-PD-1. Finally, combining S64315 and anti-PD-1 significantly slowed tumor growth compared to either agent alone. Together, this proof-of-concept study demonstrates the potential of combining MCL1 inhibitor with anti-PD-1 in the treatment of melanoma. It justifies the further development of next generation MCL1 inhibitors to improve efficacy of ICIs in treating malignant melanoma.
 
Overall design Myeloid cells were isolated from melanoma tumors by FACS on Live/CD3-/CD19-/CD56-/CD11b+ cells, single cell libraies were prepared using the 10X genomics chromium system using the 10x 3' chemistry (library) and sequenced on novaseq 6000.
 
Contributor(s) Tobin R, Shellman Y, Brunetti T, McCarter M
Citation(s) 38459020
Submission date Dec 11, 2023
Last update date May 31, 2024
Contact name Richard Tobin
E-mail(s) richard.tobin@ucdenver.edu
Organization name University of Colorado Anschutz Medical Campus
Street address 12800 E. 19th Ave.
City Aurora
State/province Colorado
ZIP/Postal code 80045
Country USA
 
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (1)
GSM7966836 Omentum_melanoma
Relations
BioProject PRJNA1051116

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Supplementary file Size Download File type/resource
GSE249909_RAW.tar 90.8 Mb (http)(custom) TAR (of H5, RDS)
SRA Run SelectorHelp
Raw data are available in SRA

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