CXC chemokine ligand-10 promotes the accumulation of monocyte-like myeloid-derived suppressor cells by activating p38 MAPK signaling under tumor conditions.

CXC chemokine ligand-10 (CXCL10) is a small (10 kDa) secretory protein in the CXC subfamily of cytokines. CXCL10 has been reported to play an important role in antitumor immunity as a chemotactic factor. Tumor development is always accompanied by the formation of an immunosuppressive tumor microenvironment, and the role of CXCL10 in tumor immunosuppression remains unclear. Here, we reported that CXCL10 expression was significantly upregulated in mice with melanoma, and tumor cells secreted large amounts of CXCL10. Myeloid-derived suppressor cells (MDSCs) are an important part of the immunosuppressive tumor microenvironment. Our results showed that CXCL10 promoted the proliferation of monocyte-like (mo)-MDSCs by activating the p38 MAPK signaling pathway through CXCR3, which led to the abnormal accumulation of mo-MDSCs under tumor conditions. This finding provides a new understanding of the mechanism by which a tumor-induced immunosuppressive microenvironment forms and suggests that CXCL10 could be a potential intervention target for slowing tumor progression.

CXCL10 conditions alveolar macrophages within the premetastatic niche to promote metastasis.

Formation of the premetastatic niche is triggered by primary tumors and contributes to cancer metastasis. Evidence indicating the roles of macrophages in metastatic niche formation and organ-specific metastatic tropism has been steadily accumulating. However, the role of tissue-resident macrophages in the establishment of the premetastatic niche is not clearly defined. Here, we report that alveolar macrophages (AMs), which are lung tissue-resident macrophages, play a critical role in initiating the recruitment of monocytic myeloid-derived suppressor cells (mo-MDSCs) and the subsequent premetastatic niche formation by increasing CCL12 expression. We found that CXCL10 can induce CCL12 expression by activating CXCR3 and TLR4 in AMs. CXCR3/TLR4 deficiency or inhibition of its activity reduces CCL12 expression in AMs and subsequent mo-MDSC recruitment to the premetastatic niche, thereby attenuating lung metastasis. In addition, Ube2o is a negative modulator of CXCL10-induced CCL12 expression. Downregulation of Ube2o in AMs under tumor conditions enhances TAK1-NF-κB/ERK/JNK signaling and CXCL10-induced CCL12 expression by promoting TRAF6 polyubiquitination and inhibiting DDX3X degradation. Targeting mo-MDSC recruitment via the CXCL10-CXCR3/TLR4-CCL12 axis in AMs may have therapeutic potential for suppressing lung metastasis.

MicroRNA 449c Mediates the Generation of Monocytic Myeloid-Derived Suppressor Cells by Targeting STAT6.

Myeloid-derived suppressor cells (MDSCs) promote tumour progression by contributing to angiogenesis, immunosuppression, and immunotherapy resistance. Although recent studies have shown that microRNAs (miRNAs) can promote the expansion of MDSCs in the tumour environment, the mechanisms involved in this process are largely unknown. Here, we report that microRNA 449c (miR-449c) expression was upregulated in myeloid progenitor cells upon activation of C-X-C motif chemokine receptor 2 (CXCR2) under tumour conditions. MiR-449c upregulation increased the generation of monocytic MDSCs (mo-MDSCs). The increased expression of miR-449c could target STAT6 mRNA in myeloid progenitor cells to shift the differentiation balance of myeloid progenitor cells and lead to an enhancement of the mo-MDSCs population in the tumour environment. Thus, our results demonstrate that the miR-449c/STAT6 axis is involved in the expansion of mo-MDSCs from myeloid progenitor cells upon activation of CXCR2, and thus, inhibition of miR-449c/STAT6 signalling may help to attenuate tumour progression.

Clinical relevance of systemic monocytic-MDSCs in patients with metastatic breast cancer.

The overall aim of this prospective study was to delineate the role of monocytic myeloid-derived suppressor cells (Mo-MDSCs) in patients with metastatic breast cancer (MBC). MDSCs are a heterogeneous group of immunosuppressive cells often enriched in different malignancies which hold prognostic and predictive value for clinical outcomes. Here, we assessed the clinical significance of Mo-MDSCs in 54 patients with de novo or distant recurrent MBC. We show that high levels of Mo-MDSCs significantly correlated with de novo MBC (metastatic disease at initial diagnosis), estrogen receptor (ER) negativity, and liver- and bone metastasis. A trend towards an association between high levels of Mo-MDSCs and survival (P = 0.053) was also found in patients with distant recurrent ER-positive MBC. We therefore propose that an increased population of Mo-MDSCs may be related to the metastatic or immunoregulatory switch associated with transition to a more systemic disease. Our data imply that high levels of systemic Mo-MDSCs represent patients with more aggressive disease and worse outcome.

Roles of Myeloid-Derived Suppressor Cell Subpopulations in Autoimmune Arthritis.

Emerging evidence suggests the promise of the use of myeloid-derived suppressor cells (MDSCs) in inflammatory disorders based on their unique immune-intervention properties. However, the roles of MDSCs in autoimmune arthritis are not completely understood. Indeed, their immunosuppressive functions in arthritic conditions remain controversial, with heterogeneity among MDSCs and differential effects among subpopulations receiving much attention. As a result, it is necessary to determine the roles of MDSC subpopulations in autoimmune arthritis to clarify their diagnostic and therapeutic potential. Interestingly, in the inflammation niche of autoimmune arthritis, each MDSC subpopulation can exhibit both alternatives of a given characteristic. Moreover, polymorphonuclear MDSCs (PMN-MDSCs) are likely to be more suppressive and stable compared with monocytic MDSCs (MO-MDSCs). Although various important cytokines associated with the differentiation of MDSCs or MDSC subpopulations from immature myeloid precursors, such as granulocyte colony-stimulating factor (G-CSF), have been largely applied in external inductive systems, their roles are not entirely clear. Moreover, MDSC-based clinical treatments in rheumatoid arthritis (RA) continue to represent a significant challenge, as also reported for other autoimmune diseases. In this review, we describe the effects and actions of MDSC subpopulations on the development of autoimmune arthritis and analyze several types of MDSC-based therapeutic strategies to provide comprehensive information regarding immune networks and a foundation for more effective protocols for autoimmune arthritis.

Increased Percentage of mo-MDSCs in Human Peripheral Blood May Be a Potential Indicator in the Diagnosis of Breast Cancer.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are heterogeneous cell groups that suppress T-cell responses in cancer patients and animal models. The objective of this study was to explore and evaluate the applicability of monocytic MDSCs (mo-MDSCs) in diagnosing breast cancer (BC). METHODS: In this study, we analyzed the percentage of mo-MDSCs in freshly isolated peripheral blood of patients with BC or benign tumors (BT) of the breast and healthy donors by flow cytometry. RESULTS: We found the percentage of mo-MDSCs to be 2.60 ± 0.95% in healthy donors, 2.94 ± 0.82% in BT patients, and 3.89 ± 1.35% in BC patients. The percentage of circulating mo-MDSCs was significantly increased in BC patients, and this was positively correlated with clinical stage. Receiver operating characteristic curve analysis showed 80.5% sensitivity, 61.3% specificity, and a 76.6% area under the curve, suggesting a medium clinical application value of mo-MDSCs in the diagnosis of BC. CONCLUSION: Our results suggested that the percentage of circulating mo-MDSCs in human peripheral blood may be a potential indicator in the auxiliary diagnosis of BC.

Recruited monocytic myeloid-derived suppressor cells promote the arrest of tumor cells in the premetastatic niche through an IL-1ß-mediated increase in E-selectin expression.

The tumor premetastatic niche initiated by primary tumors is constructed by multiple molecular factors and cellular components and provides permissive condition that allows circulating tumor cells to successfully metastasize. Myeloid-derived suppressor cells (MDSCs), a population of immature cells in pathological conditions, play a critical role in the formation of the premetastatic niche. However, few researches are focused on the function of monocytic MDSCs (mo-MDSCs), a subtype of MDSCs, in the construction of the niche. Here, we show that the number of mo-MDSCs is significantly increased in the premetastatic lungs of tumor-bearing mice, thus promoting tumor cell arrest and metastasis. Before the arrival of tumor cells, the lung-recruited mo-MDSCs produced IL-1ß, thereby increasing E-selectin expression and promoting tumor cell arrest on endothelial cells. Depletion of mo-MDSCs in the premetastatic lungs decreased IL-1ß production, resulting in reduced E-selectin expression. In addition, compared with alveolar macrophages and interstitial macrophages, mo-MDSCs were the major source of IL-1ß expression in the premetastatic lungs. Cytokine array analyses and transwell experiments revealed that CCL12 recruits mo-MDSCs to premetastatic lungs. CCL12 knockdown in tumor-bearing mice significantly decreased mo-MDSC infiltration into the premetastatic lungs, leading to reduced E-selectin expression. Overall, the permissive conditions produced by the infiltrated mo-MDSCs correlated with increased tumor cell arrest and metastasis. These results reveal a novel role of mo-MDSCs in constructing the premetastatic niche. Thus, inhibition of mo-MDSCs infiltration may change the premetastatic niche to normal condition and attenuate tumor metastasis.

Chemotherapy-induced myeloid suppressor cells and antitumor immunity: The Janus face of chemotherapy in immunomodulation.

Tumor recurrence remains a major problem for patients with cancer, even after initial beneficial responses to standard-of-care chemotherapeutic agents. With the recent advances in immunotherapy strategies, there is growing interest in synergistically combining immunotherapy with conventional chemotherapy to achieve durable antitumor effects. In some cases, chemotherapy-induced myeloid suppressor cells represent a critical obstacle to achieving this goal.