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SET/PP2A signaling regulates macrophage positioning in hypoxic tumor regions by amplifying chemotactic responses
Shaolong Zhang1, Jingping Zhou1, Pengzhao Shang1
1School of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China.
Abstract:
Tumor-associated macrophages (TAMs) are one of the main cellular components in the tumor microenvironment (TME). In many types of solid tumors, TAMs tend to accumulate in hypoxic areas and are intimately related to poor patient prognosis. However, the underlying mechanisms by which TAMs infiltrate hypoxic tumor regions remain unclear. In this study, we report that genetic deletion of SE translocation (SET) in myeloid cells inhibited the entry of TAMs into the hypoxic tumor region and abated their proangiogenic and immunosuppressive functions, ultimately inhibiting tumor growth. Mechanistically, in response to hypoxic tumor supernatant stimulation, SET in macrophages shuttled between the nucleus and cytoplasm via the PKC-CK2α signaling axis. Cytoplasmic retention of SET increased ERK and P38 signaling by inhibiting PP2A, which promoted TAM migration into the hypoxic area and polarization toward the M2 phenotype. Therefore, we conclude that SET modulates tumor immunity by acting as a key regulator of macrophage positioning and function in the tumor.
Insights
SE translocation (SET) protein regulates tumor-associated macrophage (TAM) infiltration into hypoxic tumor regions. Deleting SET in myeloid cells inhibits TAM migration and function, ultimately suppressing tumor growth and modulating tumor immunity.
Area of Science:
- Immunology
- Cancer Biology
- Cell Biology
Background:
- Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME).
- TAM accumulation in hypoxic tumor regions correlates with poor patient prognosis.
- Mechanisms driving TAM infiltration into hypoxic areas remain largely unknown.
Purpose of the Study:
- To elucidate the role of SE translocation (SET) in regulating TAM behavior within the TME.
- To investigate the molecular mechanisms by which SET influences TAM infiltration and function.
- To assess the therapeutic potential of targeting SET in solid tumors.
Main Methods:
- Genetic deletion of SET in myeloid cells.
- Analysis of TAM infiltration into hypoxic tumor regions.
- Investigation of signaling pathways (PKC-CK2α, ERK, P38, PP2A) in macrophages.
- Assessment of TAM proangiogenic and immunosuppressive functions.
- Evaluation of tumor growth inhibition.
Main Results:
- Genetic deletion of SET in myeloid cells significantly inhibited TAM entry into hypoxic tumor regions.
- SET shuttled between the nucleus and cytoplasm in macrophages stimulated by hypoxic tumor supernatant via the PKC-CK2α axis.
- Cytoplasmic SET inhibited PP2A, enhancing ERK and P38 signaling, promoting M2 polarization and TAM migration.
- SET deletion abated TAM proangiogenic and immunosuppressive functions, leading to reduced tumor growth.
Conclusions:
- SE translocation (SET) acts as a critical regulator of macrophage positioning and function in the tumor microenvironment.
- Targeting SET in myeloid cells offers a potential strategy to inhibit tumor progression by controlling TAM infiltration and activity.
- SET modulates tumor immunity through its influence on macrophage migration, polarization, and function in hypoxic conditions.
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