An unbiased in vivo functional genomics screening approach in mice identifies novel tumor cell-based regulators of immune rejection

Casey W. Shuptrine, Reham Ajina, Elana Fertig, Sandra A. Jablonski, H. Kim Lyerly, Zachary C. Hartman, Louis M. Weiner

Research output: Contribution to journalArticle

Abstract

The clinical successes of immune checkpoint therapies for cancer make it important to identify mechanisms of resistance to anti-tumor immune responses. Numerous resistance mechanisms have been identified employing studies of single genes or pathways, thereby parsing the tumor microenvironment complexity into tractable pieces. However, this limits the potential for novel gene discovery to in vivo immune attack. To address this challenge, we developed an unbiased in vivo genome-wide RNAi screening platform that leverages host immune selection in strains of immune-competent and immunodeficient mice to select for tumor cell-based genes that regulate in vivo sensitivity to immune attack. Utilizing this approach in a syngeneic triple-negative breast cancer (TNBC) model, we identified 709 genes that selectively regulated adaptive anti-tumor immunity and focused on five genes (CD47, TGFβ1, Sgpl1, Tex9 and Pex14) with the greatest impact. We validated the mechanisms that underlie the immune-related effects of expression of these genes in different TNBC lines, as well as tandem synergistic interactions. Furthermore, we demonstrate the impact of different genes with previously unknown immune functions (Tex9 and Pex14) on anti-tumor immunity. Thus, this innovative approach has utility in identifying unknown tumor-specific regulators of immune recognition in multiple settings to reveal novel targets for future immunotherapies.

Original languageEnglish (US)
Pages (from-to)1-16
Number of pages16
JournalCancer Immunology, Immunotherapy
DOIs
StateAccepted/In press - Aug 2 2017

Fingerprint

Genomics
Triple Negative Breast Neoplasms
Neoplasms
Genes
Immunity
Tumor Microenvironment
Genetic Association Studies
RNA Interference
Immunotherapy
Genome
Gene Expression

Keywords

  • Cancer-derived resistance to immunotherapy
  • Functional genomics
  • In Vivo Genome-wide RNAi Screen
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

Cite this

An unbiased in vivo functional genomics screening approach in mice identifies novel tumor cell-based regulators of immune rejection. / Shuptrine, Casey W.; Ajina, Reham; Fertig, Elana; Jablonski, Sandra A.; Kim Lyerly, H.; Hartman, Zachary C.; Weiner, Louis M.

In: Cancer Immunology, Immunotherapy, 02.08.2017, p. 1-16.

Research output: Contribution to journalArticle

Shuptrine, Casey W. ; Ajina, Reham ; Fertig, Elana ; Jablonski, Sandra A. ; Kim Lyerly, H. ; Hartman, Zachary C. ; Weiner, Louis M. / An unbiased in vivo functional genomics screening approach in mice identifies novel tumor cell-based regulators of immune rejection. In: Cancer Immunology, Immunotherapy. 2017 ; pp. 1-16.
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