Recurrence and metastasis remain the leading cause of death in breast cancer patients due to the lack of effective treatment. A microenvironment suitable for cancer cell growth, referred to as pre-metastatic niche (PMN), is formed in distant organs before metastasis occurs. Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of immature myeloid cells with immunosuppressive effects. They can expand in large numbers in breast cancer patients and participate in the formation of PMN. MDSCs can remodel the extracellular matrix of pulmonary vascular endothelial cells and recruit cancer stem cells to promote the lung metastasis of breast cancer. Furthermore, MDSCs facilitate immune evasion of breast cancer cells to impact the efficacy of immunotherapy. It is proposed that MDSCs represent a potential therapeutic target for the inhibition of recurrence and metastasis in breast cancer. Therapeutic strategies targeting MDSCs have shown promising efficacy in preclinical studies and clinical trials. This review presents a summary of the principal factors involved in the recruitment and activation of MDSCs during the formation of PMN, and outlines MDSCs functions such as immunosuppression and the current targeted therapies against MDSCs, aiming to provide new ideas for the treatment of distant metastases in breast cancer.
Humans ; Myeloid-Derived Suppressor Cells/immunology* ; Breast Neoplasms/immunology* ; Female ; Tumor Microenvironment ; Disease Progression ; Immunotherapy/methods* ; Neoplasm Metastasis ; Neoplastic Stem Cells

Cisplatin and other platinum-based drugs are used frequently for treatment of lung cancer. However, their clinical performance are usually limited by drug resistance or toxic effects. Carnosic acid, a polyphenolic diterpene isolated from Rosemary (Rosemarinus officinalis), has been reported to have several pharmacological and biological activities. In the present study, the combination effect of cisplatin plus carnosic acid on mouse LLC (Lewis lung cancer) xenografts and possible underlying mechanism of action were examined. LLC-bearing mice were treated with intraperitoneal injection with cisplatin, oral gavage with carnosic acid, or combination with cisplatin and carnosic acid, respectively. Combination of carnosic acid and cisplatin yielded significantly better anti-growth and pro-apoptotic effects on LLC xenografts than drugs alone. Mechanistic study showed that carnosic acid treatment boosted the function of CD8 T cells as evidenced by higher IFN-γ secretion and higher expression of FasL, perforin as well as granzyme B. In the meantime, the proportion of MDSC (myeloid-derived suppressor cells) in tumor tissues were reduced by carnosic acid treatment and the mRNA levels of iNOS2, Arg-1, and MMP9, which are the functional markers for MDSC, were reduced. In conclusion, our study proved that the functional suppression of MDSC by carnosic acid promoted the lethality of CD8 T cells, which contributed to the enhancement of anti-lung cancer effect of cisplatin.
Abietanes ; administration & dosage ; Animals ; Antineoplastic Agents ; administration & dosage ; CD8-Positive T-Lymphocytes ; drug effects ; immunology ; Carcinoma, Lewis Lung ; drug therapy ; genetics ; immunology ; Cell Line, Tumor ; Cisplatin ; administration & dosage ; Drug Synergism ; Humans ; Interferon-gamma ; genetics ; immunology ; Lung Neoplasms ; drug therapy ; genetics ; immunology ; Matrix Metalloproteinase 9 ; genetics ; Mice ; Mice, Inbred C57BL ; Myeloid-Derived Suppressor Cells ; drug effects ; immunology ; Plant Extracts ; administration & dosage ; Rosmarinus ; chemistry

OBJECTIVETo explore the myeloid-derived suppressor cell (MDSC) expression in the peripheral blood and lesions of 4NQO-induced tongue carcinoma in mouse.

METHODSThe established 4NQO mouse model was used to analyze the distribution of MDSC and T cell subsets in the peripheral blood by flow cytometry. The relations of MDSC with T cell subsets and CD4⁺/CD8⁺ changes were evaluated. The distribution of MDSC in the lesions of tongues was analyzed by immu- nohistochemistry, and the expression of arginase 1 (ARG-1) in tongue tissues was detected by real-time polymerase chain reaction.

RESULTSDuring tumor progression, a significant increase was observed in the frequency of MDSC in the peripheral blood of 4NQO treated mice (P < 0.01). The frequency of MDSC was positively correlated with systemic CD3⁺CD8+T cells but negatively correlated with the CD4⁺/CD8⁺ ratio. Squamous cell carcinomas were extensively infiltrated with MDSC, whereas dysplastic area and normal tongue mucosa had only sparse MDSC infiltration. The majority of MDSCs were located in the stroma, particularly along the tumor invasive front. Moreover, 4NQO-treated mice showed significantly higher ARG-1 mRNA levels in the tumor site (P<0.01).

CONCLUSIONMDSC may contribute to oral tumor progression and represents a potential target for immunotherapy of oral cancer.

4-Nitroquinoline-1-oxide ; Animals ; Arginase ; Cell Count ; Flow Cytometry ; Mice ; Models, Animal ; Myeloid-Derived Suppressor Cells ; immunology ; Real-Time Polymerase Chain Reaction ; T-Lymphocyte Subsets ; immunology ; Tongue Neoplasms ; immunology