IKZF1 Enhances Immune Infiltrate Recruitment in Solid Tumors and Susceptibility to Immunotherapy

James C. Chen, Rolando Perez-Lorenzo, Yvonne M. Saenger, Charles G. Drake, Angela M. Christiano

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Immunotherapies are some of the most promising emergent treatments for several cancers, yet there remains a majority of patients who do not benefit from them due to immune-resistant tumors. One avenue for enhancing treatment for these patients is by converting these tumors to an immunoreactive state, thereby restoring treatment efficacy. By leveraging regulatory networks we previously characterized in autoimmunity, here we show that overexpression of the master regulator IKZF1 leads to enhanced immune infiltrate recruitment and tumor sensitivity to PD1 and CTLA4 inhibitors in several tumors that normally lack IKZF1 expression. This work provides proof of concept that tumors can be rendered susceptible by hijacking immune cell recruitment signals through molecular master regulators. On a broader scale, this work also demonstrates the feasibility of using computational approaches to drive the discovery of novel molecular mechanisms toward treatment. Immunotherapies are promising cancer treatments but are frequently stymied by tumors that evade the immune system. Here, Chen et al. computationally identify the regulators required to hijack and reactivate immune infiltrate recruitment in tumors. They show that IKZF1 expression suppresses growth in several cancers due to enhanced immune infiltrate recruitment and significantly enhances the efficacy of α-PD1 and α-CTLA4 immunotherapies. IKZF1 genomic alterations also predict poor prognosis in patient cohorts. This work demonstrates the value of computational approaches in identifying new treatment avenues.

Original languageEnglish (US)
Pages (from-to)92-103.e4
JournalCell Systems
Volume7
Issue number1
DOIs
StatePublished - Jul 25 2018
Externally publishedYes

Keywords

  • cancer genetics
  • immune checkpoint
  • immune evasion
  • immuno-oncology
  • inhibitors
  • precision medicine
  • regulatory networks
  • systems biology

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

Fingerprint

Dive into the research topics of 'IKZF1 Enhances Immune Infiltrate Recruitment in Solid Tumors and Susceptibility to Immunotherapy'. Together they form a unique fingerprint.

Cite this