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Updated: Jan 30, 2026
Enrichment and Characterization of the Tumor Immune and Non-immune Microenvironments in Established Subcutaneous Murine Tumors
Published on: June 7, 2018
The P2X7 receptor modulates immune cells infiltration, ectonucleotidases expression and extracellular ATP levels in
Elena De Marchi1, Elisa Orioli1, Anna Pegoraro1
1Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Via Luigi Borsari, 46, 44121, Ferrara, Italy.
Abstract:
In the tumor microenvironment (TME) ATP and its receptor P2X7 exert a pivotal influence on cancer growth and tumor-host interactions. Here we analyzed the different effect of P2X7 genetic deficiency versus its antagonism on response against P2X7-expressing implanted tumors. We focused on immune cell expression of ATP degrading enzymes CD39 and CD73 and in vivo measured TME's ATP. The immune infiltrate of tumors growing in P2X7 null mice shows a decrease in CD8+ cells and an increased number of Tregs, overexpressing the fitness markers OX40, PD-1, and CD73. A similar Treg phenotype is also present in the spleen of tumor-bearing P2X7 null mice and it is paralleled by a decrease in proinflammatory cytokines and an increase in TGF-β. Differently, systemic administration of the P2X7 blocker A740003 in wild-type mice left unaltered the number of tumor-infiltrating CD8+ and Treg lymphocytes but increased CD4+ effector cells and decreased their expression of CD39 and CD73. P2X7 blockade did not affect spleen immune cell composition or ectonucleotidase expression but increased circulating INF-γ. Augmented CD73 in P2X7 null mice was mirrored by a decrease in TME ATP concentration and nucleotide reduced secretion from immune cells. On the contrary, TME ATP levels remained unaltered upon P2X7 antagonism, owing to release of ATP from cancerous cells and diminished ectonucleotidase expression by CD4+ and dendritic cells. These data point at P2X7 receptor as a key determinant of TME composition due to its combined action on immune cell infiltrate, ectonucleotidases, and ATP release.
Insights
Genetic deficiency of the P2X7 receptor alters tumor microenvironment immunity, increasing regulatory T cells (Tregs). P2X7 receptor antagonism has different immune effects, highlighting its complex role in cancer.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- The tumor microenvironment (TME) is crucial for cancer progression.
- ATP and its receptor P2X7 significantly influence cancer growth and tumor-host interactions.
- Understanding the differential effects of P2X7 modulation is key to cancer therapy.
Purpose of the Study:
- To analyze the distinct effects of P2X7 genetic deficiency versus antagonism on P2X7-expressing tumors.
- To investigate the role of immune cell ectonucleotidases (CD39, CD73) and TME ATP levels.
- To elucidate the impact on immune cell infiltrate and function within the TME.
Main Methods:
- Comparison of tumor growth and immune infiltrate in P2X7 null mice versus wild-type mice treated with a P2X7 antagonist (A740003).
- Flow cytometry analysis of immune cells (CD8+, Tregs, CD4+ effector cells) and their marker expression (OX40, PD-1, CD73, CD39).
- Measurement of ATP levels in the TME and assessment of cytokine profiles (INF-γ, TGF-β).
Main Results:
- P2X7 deficiency led to decreased CD8+ T cells and increased Tregs with an exhausted phenotype in the TME.
- P2X7 antagonism in wild-type mice increased CD4+ effector cells and decreased their ectonucleotidase expression.
- P2X7 deficiency reduced TME ATP and nucleotide secretion, while antagonism did not alter TME ATP levels due to cancer cell release and altered immune cell ectonucleotidase activity.
Conclusions:
- P2X7 receptor genetic deficiency profoundly reshapes the TME immune landscape, favoring immunosuppression.
- P2X7 receptor antagonism elicits distinct immune responses, impacting effector cell function and ectonucleotidase activity.
- The P2X7 receptor is a critical regulator of TME composition, influencing immune cell infiltrate, ectonucleotidases, and ATP dynamics.
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