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Cancer Immunology Research
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Research Articles

A Genetic Screen to Identify Gain- and Loss-of-Function Modifications that Enhance T-cell Infiltration into Tumors

Laura M. Rogers, Zhaoming Wang, Sarah L. Mott, Adam J. Dupuy and George J. Weiner
Laura M. Rogers
1Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
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  • ORCID record for Laura M. Rogers
  • For correspondence: Rogers.Laura@mayo.edu
Zhaoming Wang
1Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
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Sarah L. Mott
1Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
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Adam J. Dupuy
1Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
2Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa.
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George J. Weiner
1Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
3Department of Internal Medicine, University of Iowa, Iowa City, Iowa.
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DOI: 10.1158/2326-6066.CIR-20-0056 Published September 2020
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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.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2020;8:1206–14

  • Received January 21, 2020.
  • Revision received April 14, 2020.
  • Accepted June 26, 2020.
  • Published first July 1, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 8 (9)
September 2020
Volume 8, Issue 9
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A Genetic Screen to Identify Gain- and Loss-of-Function Modifications that Enhance T-cell Infiltration into Tumors
Laura M. Rogers, Zhaoming Wang, Sarah L. Mott, Adam J. Dupuy and George J. Weiner
Cancer Immunol Res September 1 2020 (8) (9) 1206-1214; DOI: 10.1158/2326-6066.CIR-20-0056

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A Genetic Screen to Identify Gain- and Loss-of-Function Modifications that Enhance T-cell Infiltration into Tumors
Laura M. Rogers, Zhaoming Wang, Sarah L. Mott, Adam J. Dupuy and George J. Weiner
Cancer Immunol Res September 1 2020 (8) (9) 1206-1214; DOI: 10.1158/2326-6066.CIR-20-0056
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