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Related Experiment Videos

Extracellular nucleosides and nucleotides as immunomodulators.

Oliver Kepp1,2,3,4, Friedemann Loos1,2,3,4, Peng Liu1,2,3,4,5

  • 1Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.

Immunological Reviews
|October 14, 2017
PubMed
Summary

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Anticancer therapies can trigger immune responses by releasing adenosine triphosphate (ATP). However, enzymes can convert ATP to adenosine, which suppresses anti-tumor immunity by inhibiting T cells. This highlights the importance of modulating these metabolites for effective cancer immunotherapy.

Area of Science:

  • Immunology
  • Oncology
  • Biochemistry

Background:

  • Anticancer agents can induce immunogenic cell death, releasing danger signals that activate innate immune responses against tumors.
  • Extracellular adenosine triphosphate (ATP) released by tumors is crucial for attracting antigen-presenting cells and activating inflammasomes, promoting anti-tumor immunity.
  • Conversely, ectonucleotidases hydrolyze nucleotides to nucleosides, reducing immune cell activation and promoting immunosuppression via adenosine, which inhibits effector T cells.

Purpose of the Study:

  • To discuss the critical role of death metabolites, particularly ATP and adenosine, in modulating anti-tumor immunity.
  • To highlight the mechanisms by which nucleotide metabolism influences the tumor microenvironment and immune cell function.
  • To review therapeutic strategies aimed at restoring tumor immunogenicity by targeting nucleotide-dependent immunosuppression.
Keywords:
adaptive immunityanticancer chemotherapycancerimmunogenic cell death

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Main Methods:

  • Literature review and synthesis of existing research on immunogenic cell death, danger signals, and nucleotide metabolism in cancer.
  • Analysis of the biochemical pathways involving ectonucleotidases and their impact on extracellular nucleotide levels.
  • Discussion of the immunomodulatory effects of ATP and adenosine on immune cells within the tumor microenvironment.

Main Results:

  • Anticancer therapy-induced release of ATP is essential for initiating anti-tumor immune responses.
  • Ectonucleotidase activity and subsequent adenosine production create an immunosuppressive environment by inhibiting antigen-presenting cell recruitment and effector T cell function.
  • The balance of extracellular nucleotides significantly impacts the efficacy of cancer immunotherapy.

Conclusions:

  • Modulating the tumor microenvironment by targeting nucleotide metabolism, specifically the ATP-adenosine axis, is a promising strategy for enhancing cancer immunotherapy.
  • Therapeutic interventions aimed at inhibiting ectonucleotidases or blocking adenosine signaling can reinstate tumor immunogenicity and overcome treatment resistance.
  • Understanding the interplay between cell death, nucleotide metabolites, and immune cells is crucial for developing more effective cancer treatments.