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Series GSE122336 Query DataSets for GSE122336
Status Public on Jun 19, 2019
Title Single-cell profiling guided combinatorial immunotherapy for breast cancer resistance to Her2/neu and CDK4/6 targeted therapy
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Trastuzumab (Herceptin™), a humanized monoclonal antibody targeting the extracellular domain of human epidermal growth factor receptor-2 (HER2), is one of the most successful examples of targeted therapies for HER2-positive breast cancer. However, drug resistance remains daunting challenges. New combinatorial regimen of CDK4/6 inhibitors plus trastuzumab is currently under active clinical investigations. In this study, we seek to prospectively model the in vivo response to CDK4/6 inhibitor Palbociclib (Pal) plus trastuzumab (Ab) using transgenic Her2/Neu mouse model in parallel with the current clinical trial scenario. We performed single cell RNA-seqencing (Drop-seq) to profile and compare tumor cells and infiltrated immune cells derived from control, Ab+Pal sensitive/residual (APS) and resistant/progressive (APR) tumors. We revealed that although Ab+Pal treatment enhanced antigen processing, presentation and interferon signaling on tumor cells, a distinct immunosuppressive immature myeloid cells (IMCs) infiltrated in the resistant tumor microenvironment to promote resistant phenotype. Based on single cell gene set enrichment analysis (profiling) guided drug screening, we identified and evaluated a combinatorial immunotherapy regimen. We found that combinatorial immunotherapy with receptor tyrosine kinase inhibitor Cabozantinib and immune checkpoint blockades overcome Ab+Pal resistance by inhibiting IMCs and enhancing anti-tumor immunity. Moreover, our rationally designed sequential combinatorial regimens enabled durable response and sustained controlling of the emergence of acquired resistance, thus significantly improved outcomes of rapidly evolving Her2/Neu positive breast cancers. Our results implicate that single-cell RNA sequencing profiling guided combinatorial immunotherapy as a strategy to mitigate the emergence of resistance and to achieve long-term therapeutic benefit merits clinical translation.
 
Overall design Drop-seq of tumor cells and tumor infiltrating immune cells derived from FVB/N MMTV-neu202Mul mice with different treatment/phenotypes (sensitive and resistant tumors).
 
Contributor(s) Wang Q, Zhang S
Citation(s) 31444334
NIH grant(s)
Grant ID Grant title Affiliation Name
R01 CA194697 (PQD-3) Spatiotemporal Molecular Interrogation of Early Metastatic Evolution In Situ UNIVERSITY OF NOTRE DAME Siyuan Zhang
R01 CA222405 Mechanisms of neuroinflammation in brain metastasis progression UNIVERSITY OF NOTRE DAME Siyuan Zhang
Submission date Nov 08, 2018
Last update date Sep 03, 2019
Contact name Qingfei Wang
E-mail(s) qwang9@nd.edu
Organization name University of Notre Dame
Department Harper Cancer Research Institute
Lab Zhang Lab
Street address 1234 N Notre Dame Ave, Harper Hall A121
City South Bend
State/province IN
ZIP/Postal code 46617
Country USA
 
Platforms (2)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (21)
GSM3464164 Ctrl_T
GSM3464165 Ab_T
GSM3464166 Pal_T
Relations
BioProject PRJNA504662
SRA SRP168253

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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE122336_RAW.tar 48.5 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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