Yue Zhang

β-Glucan enhances antitumor immune responses by regulating differentiation and function of monocytic myeloid-derived suppressor cells

Myeloid‐derived suppressor cells (MDSCs) accumulate in tumor‐bearing hosts and play a major role in tumor‐induced immunosuppression, which hampers effective immuno‐therapeutic approaches. β‐Glucans have been reported to function as potent immuno‐modulators to stimulate innate and adaptive immune responses, which contributes to their antitumor property. Here, we investigated the effect of particulate β‐glucans on MDSCs and found that β‐glucan treatment could promote the differentiation of M‐MDSCs (monocytic MDSCs) into a more mature CD11c+ F4/80+ Ly6Clow population via dectin‐1 pathway in vitro, which is NF‐κB dependent, and the suppressive function of M‐MDSCs was significantly decreased. Treatment of orally administered yeast‐derived particulate β‐glucan drastically downregulated MDSCs but increased the infiltrated DCs and macrophages in tumor‐bearing mice, thus eliciting CTL and Th1 responses, inhibiting the suppressive activity of regulatory T cells, thereby leading to the delayed tumor progression. We show here for the first time that β‐glucans induce the differentiation of MDSCs and inhibit the regulatory function of MDSCs, therefore revealing a novel mechanism for β‐glucans in immunotherapy and suggesting their potential clinical benefit.

Correlation between the Frequency of Th17 Cell and the Expression of MicroRNA-206 in Patients with Dermatomyositis

It was reported that IL-17 had been detected in the inflammatory infiltrates of patients with DM (dermatomyositis). In this study, we investigated the frequency of Th17 cells and the expression of microRNA-206 (miR-206) in DM patients. Firstly, we observed that the frequency of Th17 cells and the expression of transcription factors were increased significantly in the PBMCs of DM patients. Secondly, we found that there was a positive correlation between the percentages of Th17 cells and serum level of CK in DM patients. And the serum concentrations of IL-6, IL-1β, TGF-β, and IL-23, the important cytokines of Th17 differentiation, were increased in DM patients. It was predicted that Krüppel-like factor 4 (KLF4) is one of the multiple targets of miR-206. We detected the expression of miR-206 in DM patients, and it was decreased in the serum and PBMCs of DM patients. The augmented expression of KLF is accompanied by the attenuated expression of miR-206. Furthermore, a negative correlation between the percentages of Th17 cells and the expression of miR-206 in DM patients has been found. Taken together, these findings suggest the attenuated expression of miR-206, and the augmented frequency of Th17 cells in DM patients.

MicroRNA-9 Regulates the Differentiation and Function of Myeloid-Derived Suppressor Cells via Targeting Runx1.

Myeloid-derived suppressor cells (MDSCs) play a critical role in tumor-associated immunosuppression, thus affecting effective immunotherapies for cancers. However, the molecular mechanisms involved in regulating the differentiation and function of MDSCs remain largely unclear. In this study, we found that inhibition of microRNA (miR)-9 promoted the differentiation of MDSCs with significantly reduced immunosuppressive function whereas overexpression of miR-9 markedly enhanced the function of MDSCs. Notably, knockdown of miR-9 significantly impaired the activity of MDSCs and inhibited the tumor growth of Lewis lung carcinoma in mice. Moreover, miR-9 regulated MDSCs differentiation by targeting the runt-related transcription factor 1, an essential transcription factor in regulating MDSC differentiation and function. Furthermore, the CREB was found to regulate miR-9 expression in MDSCs. Taken together, our findings have identified a critical role of miR-9 in regulating the differentiation and function of MDSCs.

Ficus carica Polysaccharides Promote the Maturation and Function of Dendritic Cells

Various polysaccharides purified from plants are considered to be biological response modifiers and have been shown to enhance immune responses. Ficus carica L. is a Chinese traditional plant and has been widely used in Asian countries for its anti-tumor properties. Ficus carica polysaccharides (FCPS), one of the most essential and effective components in Ficus carica L., have been considered to be a beneficial immunomodulator and may be used in immunotherapy. However, the immunologic mechanism of FCPS is still unclear. Dectin-1 is a non-toll-like pattern recognition receptor, predominately expressed on dendritic cells (DCs). Activation of DCs through dectin-1 signaling can lead to the maturation of DC, thus inducing both innate and adaptive immune responses against tumor development and microbial infection. In our study, we found that FCPS could effectively stimulate DCs, partially through the dectin-1/Syk pathway, and promote their maturation, as shown by the up-regulation of CD40, CD80, CD86, and major histocompatibility complex II (MHCII). FCPS also enhanced the production of cytokines by DCs, including IL-12, IFN-γ, IL-6, and IL-23. Moreover, FCPS-treated DCs showed an enhanced capability to stimulate T cells and promote T cell proliferation. Altogether, these results demonstrate that FCPS are able to activate and maturate DCs, thereby up-regulating the immunostimulatory capacity of DCs, which leads to enhanced T cell responses.

Decreased expression of microRNA-125a-3p upregulates interleukin-23 receptor in patients with Hashimoto’s thyroiditis

Interleukin IL-23 receptor (IL-23R) is increasingly recognized as a key checkpoint in autoimmune diseases, including Hashimoto’s thyroiditis (HT). However, the molecular mechanisms regulating IL-23R expression are still unknown. MicroRNAs have emerged as key regulators of various biological events via suppressing target mRNAs at the posttranscriptional level. In this study, we found that the IL-23R mRNA expression was increased in peripheral blood mononuclear cells from HT patients, and there was a positive correlation between the level of IL-23R mRNA and the serum level of anti-thyroglobulin antibody (TgAb). The miR-125a-3p expression was decreased and inversely correlated with elevated level of IL-23R in patients with HT. MiR-125a-3p inhibited IL-23R expression through directly targeting 3′untranslated region of IL-23R. An inverse correlation was observed between the level of miR-125a-3p and serum level of TgAb. Furthermore, we also found upregulated IL-23R expression and downregulated miR-125a-3p expression in thyroid tissues from HT patients. Taken together, our results indicate that decreased expression of miR-125a-3p was involved in the pathogenesis of Hashimoto’s thyroiditis.

Long Non-Coding RNA HOXA Transcript Antisense RNA Myeloid-Specific 1–HOXA1 Axis Downregulates the Immunosuppressive Activity of Myeloid-Derived Suppressor Cells in Lung Cancer

HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is a long non-coding RNA that has been shown to be a key regulator of myeloid cell development by targeting HOXA1. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that possess immunosuppressive function. However, the impact of HOTAIRM1 on the development of MDSCs remains unknown. In this study, we demonstrated that HOTAIRM1 was expressed in MDSCs and that overexpression of HOTAIRM1 could downregulate the expression of suppressive molecules in MDSCs. In addition, HOTAIRM1 levels were observed to be decreased in the peripheral blood cells of lung cancer patients compared with those of healthy controls. By analyzing HOTAIRM1 expression levels in different types of lung cancer, we found that HOTAIRM1 was mainly expressed in lung adenocarcinoma. Finally, it was confirmed that HOTAIRM1 could enhance the expression of HOXA1 in MDSCs and that high levels of HOXA1, the target gene of HOTAIRM1, could delay tumor progression and enhance the antitumor immune response by downregulating the immunosuppression of MDSCs. Taken together, this study illustrates that HOTAIRM1/HOXA1 downregulates the immunosuppressive function of MDSCs and may be a potential therapeutic target in lung cancer.

Particulate β-glucan regulates the immunosuppression of granulocytic myeloid-derived suppressor cells by inhibiting NFIA expression

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of cells which comprise two subsets: granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs). MDSCs involve in tumor-associated immune suppression by remarkably blocking effector T-cell activation and inducing expansion of regulatory T cells in the tumor microenvironment. The treatment that alters the suppression of MDSCs can effectively facilitate the antitumor immune responses. Recently, we showed that the whole β-glucan particles (WGPs) are capable of altering the suppression of MDSCs. However, the regulatory mechanism of MDSCs by WGP remains unknown. In this study, we found that the expression of nuclear factor I-A (NFIA), an integral transcriptional component of myeloid differentiation and lineage commitment, was inhibited by WGP in G-MDSCs. The effect of WGP on expression of NFIA was the c-jun molecule dependent via Dectin-1 pathway in vitro. Moreover, NFIA knockdown could alter the suppressive function of G-MDSCs, promote the antitumor immune responses and delay the tumor progression in tumor-bearing mice. Taken together, our results demonstrate a critical role of NFIA during WGP regulating the immunosuppression of G-MDSCs, with potential implications as an antitumor immune therapeutic approach.

IL-17A weakens the antitumor immuity by inhibiting apoptosis of MDSCs in Lewis lung carcinoma bearing mice

Myeloid-derived suppressor cells (MDSCs) weaken the antitumor immune response through the inhibition of effector T cell activity and the production of immunosuppressive factors in pathological sites. It is well established that interleukin-17A (IL-17A) has a remarkable role on the promotion of inflammation and tumor formation, and IL-17 has been implicated in the enhancement of immunosuppression of MDSCs, which consequently promotes tumor progression. A detailed study of this relationship remains elusive. In our study, we not only confirmed the promotion of IL-17 on Lewis lung carcinoma (LLC) development but also surprisingly showed that IL-17 could extend the fate and enhance the immunosuppressive effect of MDSCs through activating ERK1/2. Additionally, the effect of IL-17 on MDSCs was reversed, even in tumors by blocking ERK1/2. Interdicting the signaling molecule ERK1/2 could increase the apoptosis of MDSCs and weaken the suppressive activity of MDSCs, so that thereafter, the antitumor immunity could be restored partly. Therefore, these findings offer new insights into the importance of IL-17 and the downstream signaling factor ERK1/2 for MDSCs.

IL-17A produced by peritoneal macrophages promote the accumulation and function of granulocytic myeloid-derived suppressor cells in the development of colitis-associated cancer

It is widely acknowledged that a close relationship is between inflammation and colon cancer. Interleukin (IL)-17A and myeloid-derived suppressor cells (MDSCs) play an important role in the development of colitis-associated cancer (CAC). However, the precise changes of IL-17, MDSCs, and Th17 cells during the CAC progression have not been observed in the colorectal chronic inflammation-dependent tumor. In this study, we found the level of IL-17 was increased in pathogenic colon site during the early stage of CAC model. Further experiments showed the increased IL-17 was probably secreted by peritoneal macrophages when exposed to dextran sulfate sodium (DSS). In vitro, we found that IL-17 could enhance survival and suppressive function of granulocytic (G)-MDSCs, the subset associated with inflammation. With the development of CAC, the proportions of MDSCs and Th17 cells were continuously increased by the high level of IL-17 produced by macrophages. However, the increase of MDSCs was earlier and acuter than that of Th17 cells. Selective depletion of MDSCs not only slowed down CAC process but also significantly reduce Th17 cells in vivo. Thereafter, we demonstrated that in the development of CAC, IL-17 secreted by peritoneal macrophages could promote the accumulation of G-MDSCs, then the proportion of Th17 cells was increased, and finally promote the development of CAC.

LncRNA MALAT1 negatively regulates MDSCs in patients with lung cancer

Myeloid-derived suppressor cells (MDSCs) have strong immunosuppressive functions and contribute to the formation of the tumor microenvironment. Long non-coding (Lnc) RNAs are highly important factors associated with tumors and may be used as markers for tumor diagnosis, which is valuable for targeted therapy. LncRNA MALAT1 is expressed in various tissues and plays a critical role in cell proliferation, including tumorigenesis and metastasis. However, the role of MALAT1 in MDSCs is unclear. In this study, we observed an increased proportion of MDSCs and elevated levels of the related molecule arginase-1 (ARG-1) in peripheral blood mononuclear cells (PBMCs) obtained from lung cancer patients. The proportion of CD8+ cytotoxic T lymphocyte (CTL) was significantly decreased in PBMCs from lung cancer patients. Moreover, the proportion of CTL cells was negatively correlated with the proportion of MDSCs. Furthermore, MALAT1 levels were decreased in PBMCs from lung cancer patients. The relative expression of MALAT1 was moderate negatively correlated with the proportion of MDSCs. In vitro results indicate that the knockdown of MALAT1 significantly increased the proportion of MDSCs. Our data provide the first evidence that lncRNA MALAT1 negatively regulates MDSCs and is decreased in PBMCs from lung cancer patients.