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Stimulation of Cytoplasmic DNA Sensing Pathways In Vitro and In Vivo
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Published on: September 18, 2014

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Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer

Eileen E Parkes1, Steven M Walker1, Laura E Taggart1

  • 1Affiliations of authors: Centre for Cancer Research and Cell Biology (EEP, SMW, LET, NM, RW, KDM, NEB, KIS, MST, SM, MTH, PBM, DPH, RDK) and Northern Ireland Molecular Pathology Laboratory (MST, SM), Queens University Belfast, Northern Ireland; Almac Diagnostics, Craigavon, Northern Ireland (SMW, LET, NM, LH, DPH, RDK).

Journal of the National Cancer Institute
|October 7, 2016
PubMed
Abstract

Insights

The DNA damage response-deficient (DDRD) breast cancer subtype exhibits unique immune infiltration driven by specific chemokines and a viral response pathway. This mechanism may explain T-cell inactivity and suggests DDRD for immune checkpoint therapy selection.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • A DNA damage response-deficient (DDRD) molecular subtype of breast cancer was previously identified.
  • This subtype is characterized by interferon signaling and predicts benefit from DNA-damaging chemotherapy.
  • The current study investigates the mechanism and clinical significance of the immune response in DDRD breast cancer.

Purpose of the Study:

  • To elucidate the mechanism of immune infiltration in DDRD breast cancer.
  • To explore the clinical significance of the DDRD subtype, particularly its association with immune-checkpoint protein PD-L1.
  • To understand the role of the cGAS/STING pathway in DDRD-associated immune signaling.

Main Methods:

  • Immunohistochemistry (IHC) was used to analyze immune infiltration in 184 breast cancer samples.
  • Isogenic cell lines (DDRD-positive and -negative) were employed to study chemokine release and PBMC migration.
  • Association between DDRD subtype, PD-L1 expression, and the cGAS/STING pathway activation was investigated.

Main Results:

  • DDRD tumors showed significant CD4+ and CD8+ lymphocytic infiltration.
  • DDRD cells overexpressed CXCL10 and CCL5 chemokines, attracting PBMCs.
  • Increased cytosolic DNA and constitutive activation of the cGAS/STING/TBK1/IRF3 pathway were observed in DDRD cells, linked to cell cycle and PD-L1 expression.

Conclusions:

  • A novel mechanism of immune infiltration in DDRD tumors, independent of neoantigens, is proposed.
  • The activated pathway and PD-L1 expression may explain reduced T-cell cytotoxicity in DDRD tumors.
  • DDRD subtype warrants exploration for patient stratification in immune checkpoint-based therapies.

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