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Published on: November 28, 2015
Cyclin G2 reverses immunosuppressive tumor microenvironment and potentiates PD-1 blockade in glioma
Sen Li1, Chenyang Zhao1, Jinlan Gao1
1The Research Center for Medical Genomics, Key Laboratory of Medical Cell Biology, Ministry of Education, School of Life Science, China Medical University, No.77 Puhe Road, Shenyang North New Area, Liaoning Province, Shenyang, People's Republic of China.
Background:
Expression of aberrant cyclin G2 is a key factor contributing to cancer biological processes, including glioma. However, the potential underlying mechanisms of cyclin G2 in the glioma tumor immune microenvironment remain unclear.
Methods:
Co-immunoprecipitation (co-IP), in situ proximity ligation assay (PLA), and in vitro kinase assay were conducted to reveal the underlying mechanism by which cyclin G2 regulates Y10 phosphorylation of LDHA. Further, the biological roles of cyclin G2 in cell proliferation, migration, invasion capacity, apoptosis, glycolysis, and immunomodulation were assessed through in vitro and in vivo functional experiments. Expressions of cyclin G2 and Foxp3 in glioma specimens was determined by immunohistochemistry.
Results:
In this study, we found that cyclin G2 impeded the interaction between LDHA and FGFR1, thereby decreasing Y10 phosphorylation of LDHA through FGFR1 catalysis. Cyclin G2 inhibited proliferation, migration, invasion capacity, and glycolysis and promoted apoptosis glioma cells via suppressing Y10 phosphorylation of LDHA. Moreover, we further verified that cyclin G2 reversed the immunosuppressive to antitumor immune microenvironment through inhibiting lactate production by glioma cells. Besides, cyclin G2 potentiated PD-1 blockade and exerted strong antitumor immunity in the glioma-bearing mice model.
Conclusions:
Cyclin G2 acts as a potent tumor suppressor in glioma and enhances responses to immunotherapy. Our findings may be helpful in selecting glioma patients for immunotherapy trials in the future.
Insights
Cyclin G2 acts as a tumor suppressor in glioma by inhibiting proliferation and promoting apoptosis. It also enhances anti-tumor immunity and improves responses to PD-1 blockade immunotherapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Aberrant cyclin G2 expression is implicated in glioma development.
- The role of cyclin G2 in the glioma tumor immune microenvironment is not well understood.
Purpose of the Study:
- To elucidate the mechanism of cyclin G2 in regulating the glioma tumor immune microenvironment.
- To investigate the biological functions of cyclin G2 in glioma progression and immunomodulation.
Main Methods:
- Co-immunoprecipitation, in situ proximity ligation assay, and kinase assays were used to study cyclin G2's regulation of LDHA phosphorylation.
- In vitro and in vivo experiments assessed cyclin G2's effects on glioma cell behavior and immune responses.
- Immunohistochemistry was employed to examine cyclin G2 and Foxp3 expression in glioma specimens.
Main Results:
- Cyclin G2 inhibits LDHA Y10 phosphorylation by impeding the LDHA-FGFR1 interaction.
- Cyclin G2 suppresses glioma cell proliferation, migration, invasion, and glycolysis while promoting apoptosis.
- Cyclin G2 reverses the immunosuppressive tumor microenvironment by reducing lactate production and enhances PD-1 blockade efficacy.
Conclusions:
- Cyclin G2 functions as a tumor suppressor in glioma.
- Cyclin G2 enhances glioma patient responses to immunotherapy, suggesting its potential as a predictive biomarker.
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