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Docking protein-1 promotes inflammatory macrophage signaling in gastric cancer

Tong Li1,2, Beifang Li2, Asgharpour Sara2

  • 1Institute of Digestive Disease and The Dept. of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Oncoimmunology
|October 25, 2019
PubMed

Insights

Targeting Docking protein-1 (DOK1) may enhance cancer immunotherapy. DOK1 reprogramming of macrophages boosts innate immune response against Epstein Barr Virus-positive gastric cancer.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Docking protein-1 (DOK1) is a tumor suppressor often lost in cancer cells.
  • DOK1 influences immune receptor activity in the tumor microenvironment's stroma cells.
  • DOK1 expression patterns vary in gastric cancer, with downregulation in tumor cells and upregulation in Epstein Barr Virus-positive (EBV+) cases.

Purpose of the Study:

  • To investigate the potential of targeting DOK1 for cancer immunotherapy.
  • To explore the role of DOK1 in the tumor microenvironment and its interaction with immune cells, particularly macrophages.
  • To determine if DOK1 modulation can enhance anti-cancer immune responses.

Main Methods:

  • Analysis of DOK1 mRNA and protein expression in gastric cancer patient samples (n=249).
  • Investigating DOK1 induction and functional effects in macrophages derived from human monocytic leukemia cell lines.
  • Co-culture experiments with DOK1-expressing macrophages and gastric cancer cells.
  • Assessing DOK1's effect on programmed-cell-death-ligand-1 (PD-L1) expression in monocytes.

Main Results:

  • DOK1 was downregulated in gastric cancer cells but upregulated in EBV+ cases, correlating with macrophage-related genes and PD-L1.
  • High DOK1 in stroma cells predicted poor prognosis and correlated with inducible nitric oxide synthase in tumor-associated macrophages.
  • In macrophages, DOK1, inducible by peroxisome proliferator-activated receptor-gamma (PPARγ) agonists, promoted an inflammatory phenotype, augmented nuclear factor-κB (NF-κB) activity, and reduced PD-L1 expression.
  • DOK1+ macrophages enhanced gastric cancer cell death in co-cultures and reduced PD-L1 in primary monocytes.

Conclusions:

  • DOK1 plays a complex role in gastric cancer, influencing both tumor cells and the immune microenvironment.
  • Modulating DOK1 in myeloid cells can reprogram them towards an anti-tumorigenic, inflammatory phenotype.
  • Targeting DOK1 offers a potential therapeutic strategy to enhance innate immunity against EBV+ gastric cancer.
Keywords:
DOK1Gastric cancerPD-L1PPARmacrophage

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