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, George J. Weiner

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1206-1214
Number of pages9
JournalCancer Immunology Research
Volume8
Issue number9
DOIs
StatePublished - Sep 1 2020

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Fingerprint Dive into the research topics of 'A genetic screen to identify gain- And loss-of-function modifications that enhance T-cell infiltration into tumors'. Together they form a unique fingerprint.

Cite this