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Series GSE53388 Query DataSets for GSE53388
Status Public on Mar 14, 2014
Title Immunotherapy Targets in Tumors
Organism Mus musculus
Experiment type Expression profiling by array
Summary Recent work has shown that cytotoxic T cells play a central role in immune-mediated control of cancers1-3, and monoclonal antibodies that target inhibitory receptors on T cells can induce significant clinical benefit in patients despite advanced disease4-6. However, many of the regulatory pathways that result in loss of T cell function within immunosuppressive tumors remain unknown. Here we show that such regulatory mechanisms can be systematically discovered in vivo in the tumor microenvironment. We devised a pool shRNA screening approach aimed at identifying genes that block the function of tumor-infiltrating CD8 T cells. We postulated that shRNAs targeting key inhibitors would enable robust T cell infiltration and proliferation in tumors, despite multiple inhibitory signals. Candidate shRNAs were discovered by transfer of shRNA-transduced T cells into tumor-bearing mice, followed by deep sequencing to quantify the representation of all hairpins in tumors and lymphoid organs. A subset of shRNAs induced T cell accumulation in tumors but not the spleen, demonstrating feasibility of discovering shRNAs with differential action across tissues. One of the targets was Ppp2r2d, a regulatory subunit of the family of PP2A phosphatases7. Control shRNA-transduced T cells underwent apoptosis upon recognition of melanoma cells, while Ppp2r2d shRNA-transduced T cells accumulated in tumors due to enhanced proliferation and reduced apoptosis. Ppp2r2d shRNAexpressing T cells also significantly delayed tumor growth. This in vivo approach has wide applications to dissect complex immune functions in relevant tissue microenvironments.
 
Overall design OT-I derived T cells were transduced with shRNA's and adoptively transferred to B16 tumor bearing mice. Following incubation the T cells were purified from either tumors or spleens. The shRNA's targeted either a control gene (LacZ) or one of 5 selected genes found to regulate the presence of T cells in tumors vs in spleen
 
Contributor(s) Zhou P, Shaffer DR, Alvarez Arias DA, Nakazaki Y, Pos W, Torres AJ, Cremasco V, Dougan SK, Cowley GS, Elpek K, Brogdon J, Lamb JR, Turley S, Ploegh HL, Root DE, Love JC, Dranoff G, Hacohen N, Cantor H, Wucherpfennig KW
Citation(s) 24476824
Submission date Dec 17, 2013
Last update date Feb 11, 2019
Contact name John R Walker
E-mail(s) [email protected]
Phone 858-812-1636
Organization name Genomics Institute of the Novartis Research Foundation
Lab Genetics Core
Street address 10675 John Jay Hopkins
City San Diego
State/province CA
ZIP/Postal code 92121
Country USA
 
Platforms (1)
GPL1261 [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array
Samples (36)
GSM1290674 Adoptive transfer of OT-I derived T cells transduced with shRNA into B16 tumor bearing mice_1-sp1
GSM1290675 Adoptive transfer of OT-I derived T cells transduced with shRNA into B16 tumor bearing mice_1-sp2
GSM1290676 Adoptive transfer of OT-I derived T cells transduced with shRNA into B16 tumor bearing mice_1-sp3
Relations
BioProject PRJNA231899

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE53388_RAW.tar 129.6 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table
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