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Phosphodiesterase 4A confers resistance to PGE2-mediated suppression in CD25+ /CD54+ NK cells

Ziqing Chen1, Ying Yang1,2,3, Shi Y Neo1

  • 1Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

EMBO Reports
|January 22, 2021
PubMed

Insights

Interleukin-15 (IL-15) enhances natural killer (NK) cell persistence in the tumor microenvironment by promoting resistance to prostaglandin E2 (PGE2) suppression. This IL-15-induced NK cell subset shows improved tumor infiltration, offering potential for cancer immunotherapy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Cell Therapy

Background:

  • Poor persistence of tumor-infiltrating natural killer (NK) cells correlates with adverse cancer prognoses.
  • The tumor microenvironment contains immunosuppressive factors like prostaglandin E2 (PGE2), which hinder NK cell function and survival.

Purpose of the Study:

  • To determine if modulating the cytokine environment with IL-2 or IL-15 can make lung cancer-associated NK cells resistant to PGE2-mediated suppression.
  • To explore the potential of specific NK cell subsets for adoptive cell therapy in lung cancer.

Main Methods:

  • Analysis of Cancer Genome Atlas (TCGA) data to correlate NK cell signatures with patient survival and prostaglandin E synthase (PTGES) levels.
  • In vitro and in vivo experiments to assess the effects of IL-2 and IL-15 on NK cell phenotype, function, and tumor infiltration in the presence of PGE2.

Main Results:

  • High NK cell gene signatures are linked to better overall survival in patients with elevated PTGES.
  • IL-15, unlike IL-2, generates CD25+/CD54+ NK cells with enhanced mTOR activity and PDE4A expression.
  • These IL-15-expanded NK cells retain function against PGE2 and exhibit improved lung adenocarcinoma tumor infiltration.

Conclusions:

  • IL-15 promotes a distinct NK cell population (CD25+/CD54+) resistant to PGE2 suppression, crucial for overcoming the immunosuppressive tumor microenvironment.
  • Enriching for CD25+/CD54+ NK cells via IL-15 warrants consideration for developing effective adoptive cell therapies for lung cancer.
Keywords:
cancercell therapynatural killer cellsphosphodiesteraseprostaglandin-E2

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