Function of myeloid-derived suppressor cells and strategy of reversal immunosuppression / 中国肿瘤生物治疗杂志

@#Myeloid-derived suppressor cells (MDSCs) are a group of highly heterogeneous immunosuppressive cells produced in the bone marrow, which accumulate in large amounts under pathological conditions such as malignant tumors. MDSCs are the significant cell subsets that reduce patients' response to traditional treatment and promote tumor progression. In recent years, immune checkpoint blockade and adoptive transfusion of engineered T cells have significantly prolonged the survival of many patients with advanced malignant tumors, but the effective rate from 15% to 40% in some solid tumors including lung cancer, colorectal cancer etc., which is closely related to the immunosuppressive microenvironment in solid cancers. With the accumulation in tumor microenvironment, MDSCs reduce the anti-tumor immune response of patients by inhibiting T cell or NK cell proliferation and function, which is the key mechanism for patients tolerating to immunotherapy. Therefore, clarifying the accumulation and functional characteristics of MDSCs is an important research direction to explore the improvement of restoring immunotherapy. This article will systematically elaborate the regulatory mechanism of MDSC production, aggregation and immunosuppressive function, and outline the latest research progress of targeted MDSC therapy

Research Progress of Different Subtypes of Myeloid-derived Suppressor Cells and Traditional Chinese Medicine Regulation Effect in Tumor Microenvironment / 中国实验方剂学杂志

The diagnosis and treatment methods for cancer are being improved continually, but the mortality of cancer still remains high. At present, the academic circle has realized deficiency of existing treatment ideas, and the concept of cancer cells has been gradually changed from "extremely extinct" to "peaceful coexistence". The concept of "survival with tumors" is universally accepted in the cancer academia. The tumor microenvironment is the place where tumor cells survive and develop. Therefore, regulation of the tumor microenvironment has become an important new strategy for tumor treatment. Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous cells that have immunosuppressive properties on T cells in the tumor microenvironment and play an important role in tumor immune escape. Now, therapy with MDSCs in the tumor microenvironment as the treatment targets also provides new ideas for the tumor treatment. As MDSCs subpopulations are similar with neutrophils and monocytes, they can be divided into two major subtypes:granulocyte-like myeloid-derived suppressor cells (G-MDSCs) and monocyte-myeloid-derived suppressor cells(M-MDSCs). But how to differ these two subtypes from neutrophils and monocytes. What are the differences in the functional characteristics of different subtypes of MDSCs. How do they accumulate, differentiate, and exert immunosuppressive effects through different pathways. Traditional Chinese medicine(TCM) has always been good at modulating the body's microenvironment. More and more researches have shown that, the recruitment, amplification and activation of MDSCs can be effectively inhibited by TCM compound and its active ingredients, providing scientific basis for Chinese medicine targeting MDSCs in the tumor microenvironment. However, which specific pathways could regulate G-MDSCs or M-MDSCs is still in need of further studies. Most previous literature focus on the overall level of MDSCs, while the this paper would be based on the specific subpopulations of MDSCs to clarify the biological characteristics of these two subtypes of MDSCs, so as to achieve more precise targeted therapy in the tumor microenvironment.

IL-6 promotes MDSCs infiltration and immunosuppression in breast cancer by inducing SOCS3 deficiency / 中国肿瘤生物治疗杂志

@# Objective: To investigate the immunosuppressive effect and underlying molecular mechanisms of Myeloid-derived suppressor cells (MDSCs) on T cells activity through IL-6activatingSTAT3/IDO signaling pathway. Methods: Twenty pairs of cancer tissues and the corresponding adjacent normal tissues from breast cancer patients treated at Tianjin Medical University Cancer Institute and Hospital from November 2015 to February 2016 were collected for this study; in the meanwhile, peripheral blood samples from 40 healthy donorswere also collected. CD33+ cells in tumor tissues and CD33+ CD14 + cells in peripheral blood of helthy donors were sorted out with MicroBeads technology. CD33+ cells were in vitro co-cultured with breast cancer cell line MDA-MB-231 to induce MDSCs. Flow cytometry was used to detect the proportion of CD45+ CD13+CD33+CD14-CD15- MDSCs.Western Blotting was used to detect the expression ofSOCS1，SOCS3, JAK1, JAK2, TYK2, STAT1, STAT3 and their phosphorylation levels. qRT-PCR was used to detect the expression of IL-6 and SOCS1-3. CCK8 was used to detect the T cell proliferation. Annexin V staining was used to detect T cell apoptosis. ELISA was used to detect IL-10 and IFN-γ secreted by T cells. Results: There were MDSCs infiltration in all 20 cases of breast cancer tissues for different levels (15.3%~58.1%), with a mean level of (29.82± 11.46%); the infiltration of IL-6high group was significantly higher than that of the IL-6low group [（13.75±3.44） % vs（4.31±1.50） %， P< 0.05], indicating that IL-6 expression was positively correlated with MDSCs infiltration (R2=0.4399, P<0.01). In vitro experiments showed that tumor-derived IL-6 significantly promoted the generation and immunosuppressive activity of MDSCs (P<0.05), which could be reversed by the blocking of IL-6. In the meanwhile, the expression of SOCS3 in MDSCs that induced in vitro was absent, which can be inhibited by blocking IL-6 (P<0.05). Conclusion: The study has demonstrated that tumor-derived IL-6 stimulates the continuous activation of the JAK/STAT signaling pathway and the absence of SOCS3 expression in MDSCs, thereby promoting the infiltration, generation and immunological activity of MDSCs. Therefore, IL-6 signaling pathway can be used as therapeutic target to weaken MDSCs generation and reverse MDSCs activity.

TLR/MyD88-mediated Innate Immunity in Intestinal Graft-versus-Host Disease

Graft-versus-host disease (GHVD) is a severe complication after allogeneic hematopoietic stem cell transplantation. The degree of inflammation in the gastrointestinal tract, a major GVHD target organ, correlates with the disease severity. Intestinal inflammation is initiated by epithelial damage caused by pre-conditioning irradiation. In combination with damages caused by donor-derived T cells, such damage disrupts the epithelial barrier and exposes innate immune cells to pathogenic and commensal intestinal bacteria, which release ligands for Toll-like receptors (TLRs). Dysbiosis of intestinal microbiota and signaling through the TLR/myeloid differentiation primary response gene 88 (MyD88) pathways contribute to the development of intestinal GVHD. Understanding the changes in the microbial flora and the roles of TLR signaling in intestinal GVHD will facilitate the development of preventative and therapeutic strategies.

MDSCs are upregulated in PSGL-1-deficient mice / 中国比较医学杂志

Objective PSGL-1 is specifically expressed in leucocytes.The aim of this study was to explore the changes of myeloid-derived suppressor cells (MDSCs) in the spleen and bone marrow in PSGL-1-deficient mice.Methods PSGL-1 -/-mice were used in the experiment.After identification of the offsprings, flow cytometry was used to test the expression of CD11b and Gr-1 in C57 and PSGL-1 -/-mice.Results Compared with the C57 mice, the expression of MDSCs was up-regulated in the PSGL-1-deficient mice ( P <0.001).Conclusion The expression of MDSCs is upregulated in PSGl-1-deficient mice.

Myeloid-derived suppressor cells and tumor immune escape / 中国肿瘤生物治疗杂志

Myeloid-derived suppressor cells(MDSCs) are heterogeneous cells derived from myeloid progenitor cells and immature myeloid cells(IMCs) in bone marrow;they are the progenitors of dendritic cells(DCs),macrophages and granulocytes.MDSCs proliferate in the blood,spleen,and tumor tissues in tumor-bearing mice and in the peripheral blood and tumor tissues in patients with cancer.MDSCs prevent tumors from attacks by body immunosurveillance and promote tumors progression through inhibiting both innate and adaptive antitumor immunity by a variety of pathways;they are recruited to the peripheral tissues from bone marrow and exert their inhibitory effects on antitumor immunity after activation in peripheral tissues.Chronic inflammation-related cytokines produced by tumors play crucial roles in the recruitment and activation of MDSCs.Progress has been made in antitumor therapies targeting MDSCs.But it has only been 10 years since the discovery of MDSCs,and many questions remain to be answered through experimental and clinical investigations.This review focuses on progress in MDSCs and its subsets,the recruitment and activation of MDSCs,the mechanisms of MDSCs-mediated immunosurveillance and antitumor treatment targeting MDSCs.