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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.
Abstract:
Some anticancer agents induce immunogenic cell death that is accompanied by the emission of danger signals into the tumor microenvironment, thus attracting and activating innate immune effectors and finally inducing anticancer immunity. The release of extracellular nucleosides such as adenosine triphosphate (ATP) from the tumor in response to anticancer therapy plays a pivotal role in the attraction of antigen presenting cells and the activation of inflammasome-mediated proinflammatory cascades. In contrast, the ectonucleotidase-catalyzed phosphohydrolysis of nucleotides to nucleosides reduces the extracellular availability of nucleotides, hence limiting the recruitment and activation of antigen-presenting cells. In addition, the (over-)production of nucleosides including adenosine by ectonucleotidases located on cancer cells and regulatory T cells can induce immunosuppression, as adenosine directly inhibits the proliferation and activation of effector T cells. Here, we discuss the importance of death metabolites for immunomodulation in general, and the role of the purine nucleotide ATP and its derivative adenosine in particular. In addition, we provide an overview on therapeutic interventions that reinstate tumor immunogenicity in conditions where nucleotide-dependent immunostimulation is obstructed.
Insights
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.
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.