Journal article
A Genetic Screen to Identify Gain- and Loss-of-Function Modifications that Enhance T-cell Infiltration into Tumors
Cancer immunology research, Vol.8(9), pp.1206-1214
09/01/2020
DOI: 10.1158/2326-6066.CIR-20-0056
PMCID: PMC7483799
PMID: 32611665
Abstract
T-cell-mediated cancer immunotherapies, including anti-PD-1 and T cells expressing chimeric antigen receptors (CAR-T cells), are becoming standard treatments for many cancer types. CAR-T therapy, in particular, has been successful in treating circulating, but not solid, tumors. One challenge limiting immunotherapy success is that tumors lacking T-cell infiltration do not respond to treatment. Therefore, one potential strategy to overcome resistance is to enhance the ability of T cells to traffic into tumors. Here, we describe an unbiased in vivo genetic screen approach utilizing the Sleeping Beauty mutagenesis system to identify candidate genes in T cells that might be modified to drive intratumoral T-cell accumulation. This screen identified over 400 candidate genes in three tumor models. These results indicated substantial variation in gene candidate selection, depending on the tumor model and whether or not mice were treated with anti-PD-1, yet some candidate genes were identified in all tumor models and with anti-PD-1 therapy. Inhibition of the most frequently mutated gene, Aak1, affected chemokine receptor expression and enhanced T-cell trafficking in vitro and in vivo. Screen candidates should be further validated as therapeutic targets, with particular relevance to enhancing infiltration of adoptively transferred T cells into solid tumors.
Details
- Title: Subtitle
- A Genetic Screen to Identify Gain- and Loss-of-Function Modifications that Enhance T-cell Infiltration into Tumors
- Creators
- Laura M. Rogers - University of IowaZhaoming Wang - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IowaSarah L. Mott - University of IowaAdam J. Dupuy - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.George J. Weiner - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cancer immunology research, Vol.8(9), pp.1206-1214
- DOI
- 10.1158/2326-6066.CIR-20-0056
- PMID
- 32611665
- PMCID
- PMC7483799
- NLM abbreviation
- Cancer Immunol Res
- ISSN
- 2326-6066
- eISSN
- 2326-6074
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 9
- Grant note
- Carver College of Medicine 1 S10 OD016199-01A1; K22CA225786; P30CA086862 / NCI of the NIH University of Iowa Carver College of Medicine Iowa City Veteran's Administration Medical Center Holden Comprehensive Cancer Center P50 CA97274 / Iowa/Mayo Lymphoma SPORE
- Language
- English
- Date published
- 09/01/2020
- Academic Unit
- Anatomy and Cell Biology; Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Holden Comprehensive Cancer Center; Internal Medicine
- Record Identifier
- 9984284351802771
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