Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2
Yuan Rong1, Chun-Hui Yuan2, Zhen Qu2
1Department of Laboratory Medicine &Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan 430071, P.R. China.
Abstract:
Chemotherapies often induce drug-resistance in cancer cells and simultaneously stimulate proliferation and activation of Myeloid-Derived Suppressor Cells (MDSCs) to inhibit anti-tumor T cells, thus result in poor prognosis of patients with breast cancers. To date, the mechanism underlying the expansion of MDSCs in response to chemotherapies is poorly understood. In the present study, we used in vitro cell culture and in vivo animal studies to demonstrate that doxorubicin-resistant breast cancer cells secret significantly more prostaglandin E2 (PGE2) than their parental doxorubicin-sensitive cells. The secreted PGE2 can stimulate expansion and polymerization of MDSCs by directly target to its receptors, EP2/EP4, on the surface of MDSCs, which consequently triggers production of miR-10a through activating PKA signaling. More importantly, activated MDSCs can inhibit CD4(+)CD25(-) T cells as evidenced by reduced proliferation and IFN-γ release. In order to determine the molecular pathway that involves miR-10a mediated activation of MDSCs, biochemical and pharmacological studies were carried out. We found that miR-10a can activate AMPK signaling to promote expansion and activation of MDSCs. Thus, these results reveal, for the first time, a novel role of PGE2/miR-10a/AMPK signaling axis in chemotherapy-induced immune resistance, which might be targeted for treatment of chemotherapy resistant tumors.
Insights
Chemotherapy resistance in breast cancer is linked to increased prostaglandin E2 (PGE2) and miR-10a, which activate myeloid-derived suppressor cells (MDSCs) and suppress anti-tumor T cells, hindering treatment efficacy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Chemotherapies can induce cancer drug resistance and stimulate myeloid-derived suppressor cells (MDSCs), impairing anti-tumor immunity and leading to poor breast cancer prognosis.
- The mechanisms driving MDSC expansion during chemotherapy remain largely unknown.
Purpose of the Study:
- To elucidate the molecular mechanisms by which chemotherapy promotes MDSC expansion and immune suppression in breast cancer.
- To identify potential therapeutic targets for overcoming chemotherapy-induced immune resistance.
Main Methods:
- In vitro cell culture and in vivo animal studies were employed.
- Analysis included prostaglandin E2 (PGE2) secretion, receptor binding (EP2/EP4), PKA and AMPK signaling pathways, and miR-10a expression.
- Functional assays assessed T cell proliferation and IFN-γ release.
Main Results:
- Doxorubicin-resistant breast cancer cells secreted significantly more PGE2 than sensitive cells.
- PGE2 stimulated MDSC expansion by targeting EP2/EP4 receptors, activating PKA signaling and miR-10a production.
- miR-10a activated AMPK signaling, further promoting MDSC expansion and activation.
- Activated MDSCs inhibited CD4(+)CD25(-) T cell proliferation and IFN-γ release.
Conclusions:
- A novel PGE2/miR-10a/AMPK signaling axis is identified as a key driver of chemotherapy-induced immune resistance in breast cancer.
- Targeting this pathway presents a potential strategy for treating chemotherapy-resistant tumors and enhancing anti-tumor immunity.
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