Lung resided monocytic myeloid-derived suppressor cells contribute to premetastatic niche formation by enhancing MMP-9 expression

Abstract The tumor-derived factors involved in the expansion and accumulation of myeloid-derived suppressor cells (MDSCs) in metastatic dissemination of colorectal cancer (CRC) to the liver has not been studied. Immunohistochemistry was used to detect sphingosine-1-phosphate receptor 1 (S1PR1) and signal transducer and activator of transcription-3 (STAT3) in human colorectal tumors. IL-6 and interferon-γ were detected by enzyme-linked immunosorbent assay (ELISA). Tumor growth, invasion, and migration were evaluated by MTT, transwell, and wound healing assays, respectively. Subcutaneous tumor-bearing and CRC liver metastasis (CRLM) nude mouse models were constructed. The percentage of MDSCs was measured using multicolor flow cytometry. Western blot assay was used to evaluate S1PR1 and p-STAT3 expression in MDSCs after separation from the liver and tumor by magnetic antibody. T-cell suppression assay was detected by carboxyfluorescein succinimidyl ester (CFSE). Aberrant co-expressed S1PR1 and p-STAT3 was correlated with metachronous liver metastasis and poor prognosis in CRC. A mutual activation loop between S1PR1 and STAT3 can enhance CRC cell proliferation, migration, and invasion in vitro and in vivo. The expression of p-STAT3 and its downstream proteins can be regulated by S1PR1. p-STAT3 was the dependent signaling pathway of S1PR1 in the promotion of cell growth and liver metastasis in CRC. The level of IL-6 and the associated MDSCs stimulated by the S1PR1–STAT3 correlated with the number of liver metastatic nodes in the CRLM mouse models and patients. Increased CD14+HLA-DR−/low MDSCs from CRLM patients inhibited autologous T-cell proliferation and predict poor prognosis. The S1PR1–STAT3–IL-6–MDSCs axis operates in both tumor cells and MDSCs involved in the promotion of growth and liver metastasis in CRC. MDSCs induced by S1PR1–STAT3 in CRC cells formed the premetastatic niche in the liver can promote organ-specific metastasis.

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Targeting Myeloid-Derived Suppressor Cells for Premetastatic Niche Disruption After Tumor Resection

Annals of Surgical Oncology ◽

10.1245/s10434-020-09371-z ◽

2020 ◽

Cited By ~ 1

Author(s):

Fan Tang ◽

Yan Tie ◽

Weiqi Hong ◽

Yuquan Wei ◽

Chongqi Tu ◽

...

Keyword(s):

Extracellular Matrix ◽

Low Dose ◽

Surgical Stress ◽

Suppressor Cells ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Myeloid Derived Suppressor Cells ◽

Term Survival ◽

Premetastatic Niche

AbstractSurgical resection is a common therapeutic option for primary solid tumors. However, high cancer recurrence and metastatic rates after resection are the main cause of cancer related mortalities. This implies the existence of a “fertile soil” following surgery that facilitates colonization by circulating cancer cells. Myeloid-derived suppressor cells (MDSCs) are essential for premetastatic niche formation, and may persist in distant organs for up to 2 weeks after surgery. These postsurgical persistent lung MDSCs exhibit stronger immunosuppression compared with presurgical MDSCs, suggesting that surgery enhances MDSC function. Surgical stress and trauma trigger the secretion of systemic inflammatory cytokines, which enhance MDSC mobilization and proliferation. Additionally, damage associated molecular patterns (DAMPs) directly activate MDSCs through pattern recognition receptor-mediated signals. Surgery also increases vascular permeability, induces an increase in lysyl oxidase and extracellular matrix remodeling in lungs, that enhances MDSC mobilization. Postsurgical therapies that inhibit the induction of premetastatic niches by MDSCs promote the long-term survival of patients. Cyclooxygenase-2 inhibitors and β-blockade, or their combination, may minimize the impact of surgical stress on MDSCs. Anti-DAMPs and associated inflammatory signaling inhibitors also are potential therapies. Existing therapies under tumor-bearing conditions, such as MDSCs depletion with low-dose chemotherapy or tyrosine kinase inhibitors, MDSCs differentiation using all-trans retinoic acid, and STAT3 inhibition merit clinical evaluation during the perioperative period. In addition, combining low-dose epigenetic drugs with chemokine receptors, reversing immunosuppression through the Enhanced Recovery After Surgery protocol, repairing vascular leakage, or inhibiting extracellular matrix remodeling also may enhance the long-term survival of curative resection patients.

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

International Journal of Cancer ◽

10.1002/ijc.30538 ◽

2017 ◽

Vol 140 (6) ◽

pp. 1370-1383 ◽

Cited By ~ 33

Author(s):

Huifang Shi ◽

Juechao Zhang ◽

Xiaoqing Han ◽

Huihan Li ◽

Mingshu Xie ◽

...

Keyword(s):

Tumor Cells ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Premetastatic Niche

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Myeloid-derived suppressor cells as a target for anticancer therapy

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0012.8267 ◽

2018 ◽

Vol 72 ◽

pp. 1179-1198

Author(s):

Natalia Anger ◽

Joanna Rossowska

Keyword(s):

Myeloid Cells ◽

Suppressor Cells ◽

Immune Checkpoints ◽

Myeloid Derived Suppressor Cells ◽

Suppressor Activity ◽

Premetastatic Niche ◽

Current State ◽

Tumor Diagnostics ◽

Promote Tumor Growth ◽

Immature Myeloid Cells

Myeloid-derived suppressor cells are heterogenic immature myeloid cells, which possess suppressor activity and play an important role in both, tumor progression and metastasis. The accumulation of MDSCs is induced primarily by factors that are secreted by the tumor microenvironment, which disturb myelopoiesis that occurs in the bone marrow and enables the migration of immature myeloid cells into the tumor. MDSCs promote tumor growth by inhibiting the activity of immunocompetent cells, as well as by activating non-immunological processes, such as tumor angiogenesis, the degradation of extracellular matrix and the formation of premetastatic niche. Due to their significant impact on the development of cancer, MDSCs became clinically relevant in tumor diagnostics. In recent years, various therapeutic strategies were developed in order to inhibit the proliferation, accumulation or suppressor activity of MDSCs, as well as to render the differentiation or total depletion of these cells. The proposed therapies often combine factors that reduce MDSCs suppression with conventional chemotherapy or with immune checkpoints inhibitors. In this review, we describe the current state of knowledge about factors that enable the accumulation of MDSCs, methods of phenotypic identification of these cells, as well as the mechanisms of suppression used by them. Moreover, we provide insight into the therapeutic approaches, which aim to restore the reactivity of the immune system by reducing the suppressor effects of MDSCs.

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Pulmonary Delivery of Engineered Exosomes to Suppress Postoperative Melanoma Lung Metastasis through Preventing Premetastatic Niche Formation

10.21203/rs.3.rs-1133189/v1 ◽

2021 ◽

Author(s):

Xiaoqing Han ◽

Luopeng Bi ◽

Yunyun Wu ◽

Jiao Yan ◽

Xiaqing Wu ◽

...

Keyword(s):

T Cells ◽

Lung Metastasis ◽

Tumor Metastasis ◽

Suppressor Cells ◽

Pulmonary Delivery ◽

Mice Model ◽

Premetastatic Niche ◽

Niche Formation ◽

Targeting Peptide ◽

Organotropic Metastasis

Abstract Premetastatic niche (PMN) is a prerequisite for initiation of tumor metastasis. Targeting prevention of PMN formation in distant organs is becoming a promising strategy to suppress metastasis of primary tumor. Based on “organotropic metastasis”, melanoma tends to metastasize to lungs, where granulocytic myeloid-derived suppressor cells (G-MDSCs) recruitment in lungs significantly contributes to the PMN formation. Herein, functional exosomes (GExoI) were designed to present pulmonary targeting peptide GFE1 on the membrane and load PI3Kγ inhibitor (IPI549) inside, aiming at suppressing postoperative lung metastasis of melanoma. In postoperative mice model, intravenously injected GExoI could significantly accumulate in lungs and release IPI549 to block G-MDSCs recruitment through interfering with CXCLs/CXCR2/PI3Kγ signaling. The increased percentages of CD4+ T cells and CD8+ T cells in lungs could transform microenvironment from immunosuppression to immunostimulation, leading to metastasis inhibition. This study suggests an effective anti-metastasis strategy of targeting prevention of PMN formation through specifically blocking G-MDSCs recruitment.

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