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Relationship between the Gene Expression of Adenosine Kinase Isoforms and the Expression of CD39 and CD73
1Institute of Biology, Karelian Research Centre, Russian Academy of Sciences, Petrozavodsk, 185910 Russian Federation.
Abstract:
Tumor cells have the capacity to create an adenosine-rich immunosuppressive environment, which can interfere with antitumor immunotherapy. Approaches are currently being developed with a view to suppressing the production of adenosine or its signals. Such approaches include the use of antibodies to inhibit CD39, CD73, and adenosine-receptor antagonists. However, the abundance of enzymatic pathways that control the ATP-adenosine balance, as well as the still poorly understood intracellular adenosine regulation, makes the hoped-for success unlikely. In the present study, the enzyme adenosine kinase (ADK) needed to convert adenosine to adenosine monophosphate, thereby regulating its levels, was investigated. To do so, peripheral blood samples from patients with colorectal cancer (CRC) (n = 31) were collected with blood samples from healthy donors (n = 17) used as controls. ADK gene expression levels and those of its long (ADK-L) and short (ADK-S) isoforms were measured. The relationship between the levels of ADK gene expression and that of CD39, CD73, and A2aR genes was analyzed. It turned out that in the group of CRC patients (stages III-IV), the level of ADK-L mRNA was lower (p < 0.0011) when compared to that of the control. For the first time, an average correlation was found between the level of expression of CD39 and ADK-S (r = -0.468 at p = 0.043) and between CD73 and ADK-L (r = 0.518 at p = 0.0232) in CRC patients. Flow cytometry was used to assess the content of CD39/CD73-expressing CD8+, CD4+ and Treg lymphocytes, as well as their relationship with the level of ADK gene expression in CRC patients. But no significant correlations were found.
Insights
Tumor cells create an immunosuppressive adenosine environment. This study investigated adenosine kinase (ADK) in colorectal cancer (CRC), finding lower ADK-L levels and correlations with CD39/CD73, potentially impacting immunotherapy.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Tumor cells generate an adenosine-rich immunosuppressive environment, hindering anti-tumor immunotherapy.
- Current strategies targeting adenosine pathways (CD39, CD73, adenosine receptors) show limited success due to complex regulation.
- Adenosine kinase (ADK) plays a crucial role in regulating intracellular adenosine levels.
Purpose of the Study:
- To investigate the role of adenosine kinase (ADK) in colorectal cancer (CRC).
- To analyze ADK gene expression, including its long (ADK-L) and short (ADK-S) isoforms, in CRC patients.
- To explore the relationship between ADK expression and key genes (CD39, CD73, A2aR) involved in adenosine metabolism and immune suppression.
Main Methods:
- Gene expression analysis of ADK, ADK-L, ADK-S, CD39, CD73, and A2aR in peripheral blood samples from CRC patients (n=31) and healthy controls (n=17).
- Correlation analysis between ADK gene expression levels and CD39, CD73, and A2aR.
- Flow cytometry to assess CD39/CD73 expression on CD8+, CD4+, and Treg lymphocytes in CRC patients.
Main Results:
- ADK-L mRNA levels were significantly lower in advanced-stage CRC patients (stages III-IV) compared to controls (p < 0.0011).
- Significant correlations were observed between CD39 and ADK-S (r = -0.468, p = 0.043) and between CD73 and ADK-L (r = 0.518, p = 0.0232) in CRC patients.
- No significant correlations were found between ADK gene expression and the frequency of CD39/CD73-expressing lymphocytes.
Conclusions:
- Reduced ADK-L expression in advanced CRC suggests a potential role in disease progression or immune evasion.
- The identified correlations between ADK isoforms and CD39/CD73 highlight a complex interplay in adenosine regulation within the CRC tumor microenvironment.
- Further research is warranted to elucidate the precise mechanisms and therapeutic implications of ADK in colorectal cancer immunotherapy.
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