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Updated: Jul 29, 2025
Functional Characterization of Regulatory Macrophages That Inhibit Graft-reactive Immunity
Published on: June 7, 2017
The adaptor protein TRAF3 is an immune checkpoint that inhibits myeloid-derived suppressor cell expansion
Sining Zhu1,2, Almin I Lalani1,2, Juan Jin1,3
1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States.
Abstract:
Myeloid-derived suppressor cells (MDSCs) are aberrantly expanded in cancer patients and under other pathological conditions. These cells orchestrate the immunosuppressive and inflammatory network to facilitate cancer metastasis and mediate patient resistance to therapies, and thus are recognized as a prime therapeutic target of human cancers. Here we report the identification of the adaptor protein TRAF3 as a novel immune checkpoint that critically restrains MDSC expansion. We found that myeloid cell-specific Traf3-deficient (M-Traf3 -/-) mice exhibited MDSC hyperexpansion during chronic inflammation. Interestingly, MDSC hyperexpansion in M-Traf3 -/- mice led to accelerated growth and metastasis of transplanted tumors associated with an altered phenotype of T cells and NK cells. Using mixed bone marrow chimeras, we demonstrated that TRAF3 inhibited MDSC expansion via both cell-intrinsic and cell-extrinsic mechanisms. Furthermore, we elucidated a GM-CSF-STAT3-TRAF3-PTP1B signaling axis in MDSCs and a novel TLR4-TRAF3-CCL22-CCR4-G-CSF axis acting in inflammatory macrophages and monocytes that coordinately control MDSC expansion during chronic inflammation. Taken together, our findings provide novel insights into the complex regulatory mechanisms of MDSC expansion and open up unique perspectives for the design of new therapeutic strategies that aim to target MDSCs in cancer patients.
Insights
The adaptor protein TRAF3 restrains the expansion of myeloid-derived suppressor cells (MDSCs), which are key drivers of cancer metastasis and therapy resistance. Targeting TRAF3 offers new therapeutic strategies for cancer.
Area of Science:
- Immunology
- Cancer Biology
- Cell Signaling
Background:
- Myeloid-derived suppressor cells (MDSCs) are crucial in cancer progression, promoting immunosuppression, metastasis, and therapeutic resistance.
- Identifying regulatory mechanisms controlling MDSC expansion is vital for developing effective cancer therapies.
Purpose of the Study:
- To identify novel immune checkpoints that regulate myeloid-derived suppressor cell (MDSC) expansion.
- To elucidate the mechanisms by which TRAF3 restrains MDSC accumulation in cancer and chronic inflammation.
Main Methods:
- Utilized myeloid cell-specific Traf3-deficient mice (M-Traf3-/-) and mixed bone marrow chimeras.
- Investigated the roles of signaling pathways including GM-CSF-STAT3-TRAF3-PTP1B and TLR4-TRAF3-CCL22-CCR4-G-CSF.
- Analyzed the impact of MDSC expansion on tumor growth, metastasis, and immune cell phenotypes (T cells, NK cells).
Main Results:
- TRAF3 acts as a critical immune checkpoint restraining MDSC expansion.
- M-Traf3-/- mice showed MDSC hyperexpansion, accelerated tumor growth, and metastasis.
- TRAF3 regulates MDSC expansion through both cell-intrinsic and cell-extrinsic mechanisms involving specific signaling axes.
Conclusions:
- TRAF3 is a novel regulator of MDSC expansion, impacting cancer progression.
- Elucidated key signaling pathways controlling MDSC accumulation.
- Findings provide a basis for developing TRAF3-targeted therapies against MDSCs in cancer.
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