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Updated: Jun 3, 2026
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Altered purinergic signaling in CD73-deficient mice inhibits tumor progression
Gennady G Yegutkin1, Fumiko Marttila-Ichihara, Marika Karikoski
1MediCity Research Laboratory, University of Turku, and National Institute of Health and Welfare, Turku, Finland.
Abstract:
CD73/ecto-5'-nucleotidase dephosphorylates extracellular AMP into adenosine, and it is a key enzyme in the regulation of adenosinergic signaling. The contribution of host CD73 to tumor growth and anti-tumor immunity has not been studied. Here, we show that under physiological conditions CD73-deficient mice had significantly elevated ATPase and ADPase activities in LN T cells. In a melanoma model, the growth of primary tumors and formation of metastasis were significantly attenuated in mice lacking CD73. Among tumor-infiltrating leukocytes there were fewer Tregs and mannose receptor-positive macrophages, and increased IFN-γ and NOS2 mRNA production in CD73-deficient mice. Treatment of tumor-bearing animals with soluble apyrase, an enzyme hydrolyzing ATP and ADP, significantly inhibited tumor growth and accumulation of intratumoral Tregs and mannose receptor-positive macrophages in the WT C57BL/6 mice but not in the CD73-deficient mice. Pharmacological inhibition of CD73 with α,β-methylene-adenosine-5'-diphosphate in WT mice retarded tumor progression similarly to the genetic deletion of CD73. Together these data show that increased pericellular ATP degradation in the absence of CD73 activity in the host cells is a novel mechanism controlling anti-tumor immunity and tumor progression, and that the purinergic balance can be manipulated therapeutically to inhibit tumor growth.
Insights
Host CD73 deficiency significantly attenuates melanoma growth and metastasis by altering the tumor microenvironment. This suggests targeting CD73 activity is a promising therapeutic strategy for enhancing anti-tumor immunity and controlling cancer progression.
Area of Science:
- Immunology
- Biochemistry
- Oncology
Background:
- CD73/ecto-5'-nucleotidase regulates adenosinergic signaling by dephosphorylating AMP to adenosine.
- The role of host CD73 in tumor immunity and progression remains largely unexplored.
Purpose of the Study:
- To investigate the contribution of host CD73 to tumor growth and anti-tumor immunity.
- To explore the therapeutic potential of targeting CD73 in cancer.
Main Methods:
- Utilized CD73-deficient mice and a melanoma tumor model.
- Assessed tumor growth, metastasis, and immune cell infiltration (Tregs, macrophages).
- Measured enzyme activities (ATPase, ADPase) and gene expression (IFN-γ, NOS2).
- Employed soluble apyrase and pharmacological CD73 inhibition (α,β-methylene-adenosine-5'-diphosphate).
Main Results:
- CD73-deficient mice exhibited attenuated primary tumor growth and reduced metastasis.
- Absence of CD73 led to fewer regulatory T cells (Tregs) and mannose receptor-positive macrophages within tumors.
- Increased IFN-γ and NOS2 mRNA levels were observed in CD73-deficient tumors.
- Soluble apyrase and pharmacological CD73 inhibition mimicked the anti-tumor effects of genetic CD73 deletion in wild-type mice.
Conclusions:
- Increased extracellular ATP degradation due to host CD73 activity promotes tumor progression.
- Host CD73 deficiency enhances anti-tumor immunity by modulating the tumor microenvironment.
- Targeting CD73 activity represents a novel therapeutic avenue for cancer treatment by manipulating purinergic signaling.
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