Cancer genes disfavoring T cell immunity identified via integrated systems approach.

Journal Article (Journal Article)

Adoptive T cell therapies (ACT) have been curative for a limited number of cancer patients. The sensitization of cancer cells to T cell killing may expand the benefit of these therapies for more patients. To this end, we use a three-step approach to identify cancer genes that disfavor T cell immunity. First, we profile gene transcripts upregulated by cancer under selection pressure from T cell killing. Second, we identify potential tumor gene targets and pathways that disfavor T cell killing using signaling pathway activation libraries and genome-wide loss-of-function CRISPR-Cas9 screens. Finally, we implement pharmacological perturbation screens to validate these targets and identify BIRC2, ITGAV, DNPEP, BCL2, and ERRα as potential ACT-drug combination candidates. Here, we establish that BIRC2 limits antigen presentation and T cell recognition of tumor cells by suppressing IRF1 activity and provide evidence that BIRC2 inhibition in combination with ACT is an effective strategy to increase efficacy.

Full Text

Duke Authors

Cited Authors

  • Kishton, RJ; Patel, SJ; Decker, AE; Vodnala, SK; Cam, M; Yamamoto, TN; Patel, Y; Sukumar, M; Yu, Z; Ji, M; Henning, AN; Gurusamy, D; Palmer, DC; Stefanescu, RA; Girvin, AT; Lo, W; Pasetto, A; Malekzadeh, P; Deniger, DC; Wood, KC; Sanjana, NE; Restifo, NP

Published Date

  • August 2, 2022

Published In

Volume / Issue

  • 40 / 5

Start / End Page

  • 111153 -

PubMed ID

  • 35926468

Pubmed Central ID

  • PMC9402397

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2022.111153


  • eng

Conference Location

  • United States