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Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity

Santiago Zelenay1, Annemarthe G van der Veen1, Jan P Böttcher1

  • 1Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.

Cell
|September 8, 2015
PubMed

Insights

Cancer cells evade immune attack by producing prostaglandin E2 (PGE2). Inhibiting cyclooxygenase (COX) enzymes makes tumors vulnerable to immune control and enhances anti-cancer therapies.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Cancer cells, particularly melanoma, possess mechanisms to evade the host's anti-tumor immune responses.
  • The precise molecular pathways driving this immune evasion are not fully elucidated.
  • Tumor-promoting inflammation and immune suppression are critical factors in cancer progression.

Purpose of the Study:

  • To investigate the role of prostaglandin E2 (PGE2) in mediating immune evasion by cancer cells.
  • To determine if targeting PGE2 production can restore anti-tumor immunity.
  • To explore the potential of cyclooxygenase (COX) inhibitors as adjuncts to cancer immunotherapy.

Main Methods:

  • Utilized genetically engineered mouse models of melanoma (Braf(V600E) and Nras(G12D)), breast, and colorectal cancers.
  • Genetically ablated cyclooxygenase (COX) or prostaglandin E synthases in cancer cells.
  • Analyzed tumor immune profiles and inflammatory signatures.
  • Compared mouse data with human cutaneous melanoma biopsies.
  • Evaluated the synergistic effects of COX inhibitors and anti-PD-1 blockade in pre-clinical models.

Main Results:

  • Tumor growth in immunocompetent hosts critically depends on cancer cell production of PGE2.
  • Genetic ablation of COX or prostaglandin E synthases sensitized tumors to immune control.
  • This genetic modification shifted the tumor inflammatory profile towards anti-cancer immune pathways.
  • The observed COX-dependent inflammatory signature in mice was conserved in human melanoma.
  • Inhibition of COX synergized with anti-PD-1 blockade to eradicate tumors in pre-clinical studies.

Conclusions:

  • Prostaglandin E2 (PGE2) produced by cancer cells is a key mediator of immune suppression and tumor growth.
  • Targeting cyclooxygenase (COX) enzymes disrupts PGE2 production, rendering tumors susceptible to immune surveillance.
  • The conserved COX-driven immune evasion mechanism across species highlights its significance in cancer.
  • COX inhibitors represent a promising strategy to enhance the efficacy of current immunotherapies, such as anti-PD-1 blockade, for cancer treatment.

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