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Real Time Detection of In Vitro Tumor Cell Apoptosis Induced by CD8+ T Cells to Study Immune Suppressive Functions of Tumor-infiltrating Myeloid Cells
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Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling

Chuanhui Han1, Zhida Liu1, Yunjia Zhang2

  • 1Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.

Nature Immunology
|April 2, 2020
PubMed

Insights

High-dose radiation triggers tumor cells to suppress intrinsic DNA sensing via caspase 9 signaling, using mitochondrial DNA instead of apoptotic DNA. Combining radiation with caspase inhibitors and anti-PD-L1 therapy overcomes tumor resistance.

Area of Science:

  • Cancer biology
  • Immunology
  • Radiation oncology

Background:

  • High-dose radiation therapy generates DNA fragments that activate antigen-presenting cells but has limited intrinsic DNA sensing in tumor cells.
  • Tumor cells can suppress their own intrinsic DNA sensing mechanisms following radiation exposure.

Purpose of the Study:

  • To investigate how irradiated tumor cells suppress intrinsic DNA sensing.
  • To explore the role of caspase 9 signaling in this process.
  • To evaluate therapeutic strategies combining radiation with caspase inhibitors and immune checkpoint blockade.

Main Methods:

  • Analysis of caspase 9 signaling in irradiated tumor cells.
  • Investigation of DNA sensing pathways, distinguishing between apoptotic and mitochondrial DNA.
  • Assessment of therapeutic effects of radiation, emricasan (pan-caspase inhibitor), and anti-PD-L1 blockade in preclinical models.
  • Evaluation of programmed death-ligand 1 (PD-L1) expression and its role in adaptive resistance.

Main Results:

  • Irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing, utilizing tumor-derived mitochondrial DNA.
  • Loss of caspase 9 or mitochondrial DNA sensing in tumors abrogates the enhanced therapeutic effect of radiation.
  • Combining radiation with emricasan demonstrates synergistic therapeutic effects.
  • Loss of caspase 9 signaling induces adaptive resistance via PD-L1 upregulation, leading to tumor relapse.
  • Combined blockade of caspase 9 and PD-L1 signaling effectively controls tumors.

Conclusions:

  • Caspase 9 signaling is a critical regulator of intrinsic DNA sensing in irradiated tumor cells, with mitochondrial DNA playing a key role.
  • Targeting caspase 9 with inhibitors and combining with radiation and anti-PD-L1 therapy offers a promising strategy to overcome tumor resistance and enhance treatment efficacy.

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