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Cancer genes disfavoring T cell immunity identified via integrated systems approach

Rigel J Kishton1, Shashank J Patel1, Amy E Decker2

  • 1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA.

Cell Reports
|August 4, 2022
PubMed

Insights

This study identifies cancer genes hindering adoptive T-cell therapy (ACT) efficacy. Inhibiting BIRC2 enhances T-cell killing of cancer cells, suggesting BIRC2 as a target for improving ACT outcomes.

Area of Science:

  • Immunology
  • Cancer Biology
  • Genetics

Background:

  • Adoptive T-cell therapies (ACT) show promise but benefit a limited patient group.
  • Sensitizing cancer cells to T-cell killing could broaden ACT applications.
  • Identifying genes that shield tumors from T-cell immunity is crucial for therapeutic advancement.

Purpose of the Study:

  • To identify cancer genes that suppress T-cell immunity.
  • To discover novel targets for combination therapies with ACT.
  • To validate potential drug targets for enhancing ACT efficacy.

Main Methods:

  • Profiling gene transcripts upregulated under T-cell killing pressure.
  • Utilizing CRISPR-Cas9 screens and pathway activation libraries to identify tumor gene targets.
  • Conducting pharmacological perturbation screens to validate targets and drug combinations.

Main Results:

  • Identified BIRC2, ITGAV, DNPEP, BCL2, and ERRα as potential ACT-drug combination candidates.
  • Established that BIRC2 suppresses IRF1 activity, limiting antigen presentation and T-cell recognition.
  • Demonstrated that BIRC2 inhibition enhances ACT efficacy.

Conclusions:

  • BIRC2 is a key regulator of tumor immune evasion by inhibiting antigen presentation.
  • Targeting BIRC2 in combination with ACT represents a promising strategy to improve cancer treatment outcomes.
  • This research provides a foundation for developing novel combination therapies to expand ACT benefits.
Keywords:
CP: CancerCP: ImmunologyCRISPR screencell therapycombination immunotherapygain-of-function screenimmunotherapy resistance

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