MDSCs in bone metastasis: Mechanisms and therapeutic potential.

Bone metastasis (BM) is a frequent complication associated with advanced cancer that significantly increases patient mortality. Myeloid-derived suppressor cells (MDSCs) play a pivotal role in BM progression by promoting angiogenesis, inhibiting immune responses, and inducing osteoclastogenesis. MDSCs induce immunosuppression through diverse mechanisms, including the generation of reactive oxygen species, nitric oxide, and immunosuppressive cytokines. Within the bone metastasis niche (BMN), MDSCs engage in intricate interactions with tumor, stromal, and bone cells, thereby establishing a complex regulatory network. The biological activities and functions of MDSCs are regulated by the microenvironment within BMN. Conversely, MDSCs actively contribute to microenvironmental regulation, thereby promoting BM development. A comprehensive understanding of the indispensable role played by MDSCs in BM is imperative for the development of novel therapeutic strategies. This review highlights the involvement of MDSCs in BM development, their regulatory mechanisms, and their potential as viable therapeutic targets.

Maternal circadian rhythm disruption affects neonatal inflammation via metabolic reprograming of myeloid cells.

Disruption of circadian rhythm during pregnancy produces adverse health outcomes in offspring; however, the role of maternal circadian rhythms in the immune system of infants and their susceptibility to inflammation remains poorly understood. Here we show that disruption of circadian rhythms in pregnant mice profoundly aggravates the severity of neonatal inflammatory disorders in both male and female offspring, such as necrotizing enterocolitis and sepsis. The diminished maternal production of docosahexaenoic acid (DHA) and the impaired immunosuppressive function of neonatal myeloid-derived suppressor cells (MDSCs) contribute to this phenomenon. Mechanistically, DHA enhances the immunosuppressive function of MDSCs via PPARγ-mediated mitochondrial oxidative phosphorylation. Transfer of MDSCs or perinatal supplementation of DHA relieves neonatal inflammation induced by maternal rhythm disruption. These observations collectively demonstrate a previously unrecognized role of maternal circadian rhythms in the control of neonatal inflammation via metabolic reprograming of myeloid cells.

Bushen Antai recipe alleviates embryo absorption by enhancing immune tolerance and angiogenesis at the maternal-fetal interface via mobilizing MDSCs in abortion-prone mice.

BACKGROUND: Recurrent pregnancy loss (RPL) is a tricky puzzle that disturbs female reproduction worldwide. According to previous research, Bushen Antai recipe (BAR), a classic Chinese herbal formula widely used in clinic for miscarriage, exhibited multifaceted benefits in improving embryo implantation and attenuating early pregnancy loss. Myeloid-derived suppressor cells (MDSCs), a set of immunoregulatory cells critical in inflammation balance, get growing attention for their indispensable role in successful pregnancy. PURPOSE: To investigate the therapeutic efficacy of BAR in abortion-prone mice and explore the potential mechanisms of BAR regarding MDSCs. METHODS: RPL mice (CBA/J females paired with DBA/2 males, BALB/c males were used as the control) were administered with BAR1 (5.7 g/kg), BAR2 (11.4 g/kg), progesterone (P4), or distilled water from embryo day (D) 0.5 until D10.5. The rate of embryo absorption on D10.5 and the health status of progeny were measured. The systemic inflammatory states and the placenta-uterus milieu were assessed by serum cytokine levels, placenta-uterus architecture, and related protein expression at the maternal-fetal interface. Flow cytometry analysis was carried out to measure the frequency of MDSCs. Furthermore, we established the MDSCs-depletion mouse model by using C57BL/6 females mated with BALB/c males via intraperitoneal injection of anti-Gr-1 antibody on D6.5, while irrelative LTF antibody was used as the control. Similarly, BAR1, BAR2, P4, or distilled water was separately applied. Embryo absorption rate, systemic inflammatory states, placenta-uterus milieu, and MDSCs frequency were evaluated as mentioned above. RESULTS: Significantly, embryo absorption rate was increased with disrupted placenta-uterus milieu and exorbitant proinflammatory cytokines in RPL mice, meanwhile, MDSCs number in the placenta-uterus unit were apparently reduced (⁎⁎⁎p < 0.001). BAR treatment markedly alleviated the poor conditions above and increased MDSCs number (####p < 0.0001). Flow cytometry analysis validated the efficacy of anti-Gr-1 antibody and the raised embryo absorption rate confirmed the essentiality of MDSCs in normal pregnancy (⁎⁎p < 0.01). Besides, the placenta-uterus milieu was destroyed, accompanied by the impaired expression of immune tolerance and angiogenesis related factors in the MDSCs-depletion mice. Even though, BAR treatment reversed the embryo resorption phenotype and optimized the serum cytokine milieu, mobilizing MDSCs and rejuvenating active intercellular communication. Thereby, BAR facilitated the expression of MDSCs-related functional molecules, promoting immune tolerance and vascular remodeling at the placenta-uterus unit. CONCLUSION: We unfurled the remarkable therapeutic ability of BAR in abortion-prone mice, and this was achieved by mobilizing MDSCs, thus favoring immune tolerance and angiogenesis at the maternal-fetal interface.

Triptolide inhibits the proinflammatory potential of myeloid-derived suppressor cells via reducing Arginase-1 in rheumatoid arthritis.

Triptolide (TPT) is widely used in the treatment of rheumatoid arthritis (RA). However, its regulatory mechanisms are not fully understood. This study demonstrated that Myeloid-derived suppressor cells (MDSCs) were expanded in both RA patients and arthritic mice. The frequency of MDSCs was correlated with RA disease severity and T helper 17 (Th17) responses. MDSCs from RA patients promoted the polarization of Th17 cells in vitro, which could be substantially attenuated by blocking arginase-1 (Arg-1). TPT inhibited the differentiation of MDSCs, particularly the monocytic MDSCs (M-MDSCs) subsets, as well as the expression of Arg-1 in a dose dependent manner. Alongside, TPT treatment reduced the potential of MDSCs to promote the polarization of IL-17+ T cell in vitro. Consistently, TPT immunotherapy alleviated adjuvant-induced arthritis (AIA) in a mice model, and reduced the frequency of MDSCs, M-MDSCs and IL-17+ T cells simultaneously. The presented data suggest a pathogenic role of MDSCs in RA and may function as a novel and effective therapeutic target for TPT in RA.

Icariside II potentiates the anti-PD-1 antitumor effect by reducing chemotactic infiltration of myeloid-derived suppressor cells into the tumor microenvironment via ROS-mediated inactivation of the SRC/ERK/STAT3 signaling pathways.

BACKGROUND: Immune checkpoint blockade agents, such as anti-PD-1 antibodies, show promising antitumor efficacy but only a limited response in patients with non-small cell lung cancer (NSCLC). Icariside II (IS), a metabolite of Herba Epimedii, is a COX-2 and EGFR inhibitor that can enhance the anti-PD-1 effect. This study aimed to evaluate the antitumor effect of IS in combination with anti-PD-1 and explore the underlying mechanism. METHODS: Tumor growth was assessed in Lewis Lung Cancer (LLC) tumor-bearing mice in seven groups (control, IS 20 mg/kg, IS 40 mg/kg, anti-PD-1, IS 20 mg/kg+anti-PD-1, IS 40 mg/kg+anti-PD-1, ERK inhibitor+anti-PD-1). Tumor-infiltrating immune cells were measured by flow cytometry. The mechanisms were explored by tumor RNA-seq and validated in LLC cells through molecular biological experiments using qRT‒PCR, ELISA, and western blotting. RESULTS: Animal experiments showed that IS in combination with anti-PD-1 further inhibited tumor growth and remarkably reduced the infiltration of myeloid-derived suppressor cells (MDSCs) into the tumor compared with anti-PD-1 monotherapy. RNA-seq and in vitro experiments showed that IS suppressed the chemotactic migration of MDSCs by downregulating the expression of CXC chemokine ligands 2 (CXCL2) and CXCL3. Moreover, IS promoted reactive oxygen species (ROS) generation and inhibited the activation of SRC/ERK/STAT3 in LLC cells, which are upstream signaling pathways of these chemokines. CONCLUSION: IS potentiates the anti-PD-1 anti-tumor effect by reducing chemotactic infiltration of the myeloid-derived suppressor cell into the tumor microenvironment, via ROS-mediated inactivation of SRC/ERK/STAT3 signaling pathways.

MONOCYTIC MYELOID-DERIVED SUPPRESSOR CELL EXPANSION AFTER CARDIAC SURGERY WITH CARDIOPULMONARY BYPASS INDUCES LYMPHOCYTE DYSFUNCTION.

ABSTRACT: Cardiac surgery with cardiopulmonary bypass (CPB) is associated with an immune paresis that predisposes to the development of postoperative infections and sepsis. Among factors responsible for CPB-induced immunosuppression, circulating myeloid-derived suppressor cells (MDSCs) have been found to induce early lymphocyte apoptosis and lymphocyte proliferation inhibition. However, the mechanisms involved are not fully understood. In this study, we found that the main lymphocyte subsets decreased significantly 24 h after cardiac surgery with CBP. As expected, cardiac surgery with CPB induced a monocytic MDSC expansion associated with an increased T-cell apoptosis and decreased proliferation capacity. Noteworthy, granulocytic MDSCs remain stable. Myeloid-derived suppressor cell depletion restored the ability of T-cell to proliferate ex vivo . After CPB, indoleamine 2,3-dioxygenase activity and IL-10 plasma level were increased such as programmed death-ligand 1 monocytic expression, whereas plasma level of arginine significantly decreased. Neither the inhibition of indoleamine 2,3-dioxygenase activity nor the use of anti-programmed death-ligand 1 or anti-IL-10 blocking antibody restored the ability of T-cell to proliferate ex vivo . Only arginine supplementation restored partially the ability of T-cell to proliferate.

Mannan-Binding Lectin Deficiency Limits Inflammation-induced Myeloid-Derived Suppressor Cells Expansion via Modulating Tumor Necrosis Factor Alpha-triggered Apoptosis.

Background: Mannan-binding lectin (MBL), a soluble pattern recognition molecule in the innate immune system, is reported to be associated with the function of immune cells. Myeloid-derived suppressor cells (MDSCs) are mainly characterized by immunosuppressive activities involving several inflammatory diseases such as cancer, infection, and arthritis. Some of the factors inducing their apoptosis are known, however, mechanisms have not been identified. The underlying impact of MBL on the MDSCs especially under inflammatory conditions remains unknown. This study was designed to investigate whether MBL affects MDSCs survival during inflammation conditions. Methods: WT and MBL-deficient (MBL-/-) mice were induced on day 0 of the experiment by subcutaneous injection of complete Freund's adjuvant and then injected with incomplete Freund's adjuvant into the knee joint space under general anesthesia on day 14 to induce inflammatory arthritis. The proportions of MDSCs in the spleen and blood and the serum level of the inflammatory cytokines were measured. In vitro study, MDSCs were isolated from the bone marrow of WT and MBL-/- mice and cultured in the presence of interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF) for 5 days with or without tumor necrosis factor-alpha (TNF-α). Results: After adjuvant treatment, MBL-/- mice had a significantly lower frequency of MDSCs as well as elevated serum inflammatory cytokines levels compared to WT mice. MBL deficiency markedly inhibited the MDSCs frequency from mice bone marrow induced by IL-6 and GM-CSF in the presence of TNF-α in vitro. Mechanistic studies established that MBL inhibited MDSCs apoptosis via down-regulation of TNF-α/tumor necrosis factor-alpha receptor 1 (TNFR1) signaling pathway and subsequent caspase 3-dependent manner. Conclusion: Mannan-binding lectin deficiency inhibits myeloid-derived suppressor cells expansion via modulating TNF-α triggered apoptosis.

The effect of l-arginine supplementation and surgical trauma on the frequency of myeloid-derived suppressor cells and T lymphocytes in tumour and blood of colorectal cancer patients.

PURPOSE: l-arginine (L-arg) deficiency causes immunosuppression, but it is unknown if L-arg supplementation in colorectal cancer (CRC) patients restores immune system activity. Our objective was to investigate the effect of L-arg supplementation on the frequency of monocytic (M) and polymorphonuclear (PNM) myeloid-derived suppressor cells (M-MDSCs and PMN-MDSCs, respectively). METHODS: We enrolled 65 CRC patients (34 males, 31 females) aged 69 â€‹± â€‹10 years into a prospective, randomised, double-blind study. Twenty-eight patients received L-arg and 37 received placebo for 9 days at a dose of 10 â€‹g/day. The frequency changes in MDSC, CD4+ cells and the concentration of C-reactive protein (CRP) were assessed before supplementation with L-arg (test 1), after 9 days of supplementation (test 2), and after surgery on day 11 (test 3). RESULTS: The frequency of M-MDSC in the tumours of patients receiving L-arg supplementation was higher than in placebo-treated patients, as was the frequency of PMN-MDSC and M-MDSC in the mucosa. CRP concentration in the serum of placebo-treated patients in test 2 was higher than in test 1, and the concentration in the serum of patients with L-arg supplementation in test 2 was lower than in test 1. Moreover, the expression pattern of the argininosuccinate synthase 1 (ASS1) suggests that CRC is not auxotrophic for L-arg. CONCLUSIONS: The results of this study do not support the hypothesis that L-arg supplementation in CRC patients can reduce immunosuppression by decreasing the frequency of suppressor cells and increasing the frequency of effector CD4+ T cells.

Gansui-Banxia Decoction extraction inhibits MDSCs accumulation via AKT /STAT3/ERK signaling pathways to regulate antitumor immunity in C57bl/6 mice.

BACKGROUND: Gansui-Banxia Decoction (GSBXD) is a classic formula of traditional Chinese medical (TCM) sage Zhang Zhongjing to treat stagnation of evil heat and obstruction of qi. At present GSBXD is wildly used to treat cancerous ascites, pleural effusion, peritoneal effusion, pericardial effusion, cranial cavity effusion and several types of cancers, such as hepatocellular carcinoma (HCC) and esophageal cancer. Myeloid-derived suppressor cells (MDSCs) are a kind of immature and heterogeneous cells which can suppress lymphocytes activation by forming a suppressive environment. MDSCs accumulation in peripheral blood and tumors are closely related to the cancer stage and low survival rate of clinical patients. The antitumor immune effect of GSBXD has not received widespread attention. PURPOSE: To investigate the effects of GSBXD on MDSCs accumulation and the mediators including AKT/STAT3/ERK signaling pathways. METHODS: The chemical components of GSBXD were analyzed by UHPLC-MS, and the putative pathways of GSBXD based on Network pharmacology were predicted. Mice were vaccinated with Hepatoma 22 (H22) to establish tumor growth model, which were then administrated with GSBXD ethanol extraction (0.49 mg/kg/day, 1.75 mg/kg/day), sorafenib (60 mg/kg) or saline for 14 days. The cell morphology was evaluated by hematoxylin and eosin (H&E) staining, and immunity cells were determined through flowcytometry analysis. The levels of cytokines production in blood were evaluated by using ELISA kits. STAT3, ERK and AKT/mTOR signaling transduction associated proteins were determined by Western blot. RESULTS: GSBXD could inhibit tumor growth and splenomegaly in H22 tumor model mice. Importantly, GSBXD reduced MDSCs accumulation and differentiation, and inhibited proliferation of F4/80+ CD11b+ macrophages and apoptosis of T cells and B cells, and increased the percentage of CD 3- NK1.1+ NK cells. To better understand the active component of GSBXD, the ethanol-extraction powdered GSBXD was prepared and analyzed by UHPLC-MS. Combined with these main chemical compounds, we predicted that the anti-tumor effect of GSBXD mainly mediated PI3K-AKT and RAS-MAPK signal pathways based on Network Pharmacology. Western blot analysis of tumor tissues and MDSCs cells demonstrated that phosphorylation of AKT, ERK and STAT3 were significantly reduced, specially the activation of ERK. The levels of IL-1ß and IFN-γ were significantly decreased by ELISA analysis. CONCLUSION: GSBXD exhibited antitumor immune activity by reducing the accumulation of MDSCs in vivo, which is possible via down-regulation of AKT/STAT3/ERK signaling pathway and suppression of IL-1ß and IFN-γ.

Role of Nutritional Status in the Treatment Outcome for Esophageal Squamous Cell Carcinoma.

Undernourishment is reported to impair treatment response, further leading to poor prognosis for cancer patients. We aimed to investigate the role of nutritional status on the prognosis of squamous cell carcinoma (SCC) of the esophagus, and its correlation with anticancer immune responsiveness. We retrospectively reviewed 340 esophageal-SCC patients who completed curative treatment and received a nutrition evaluation by the Patient-Generated Subjective Global Assessment (PGSGA) score at the beginning and completion of neoadjuvant treatment at our hospital. The correlation between the nutritional status and various clinicopathological parameters and prognosis were examined. In addition, the role of nutritional status in the regulation of the anticancer immune response was also assessed in cancer patients and in a 4-nitroquinoline 1-oxide (4NQO)-induced esophageal tumor model. Our data revealed that malnutrition (patients with a high PGSGA score) was associated with advanced stage and reduced survival rate. Patients in the group with a high PGSGA score were correlated with the higher neutrophil-to-lymphocyte ratio, higher proportion of myeloid-derived-suppressor cells (MDSC) and increased IL-6 level. Furthermore, surgical resection brought the survival benefit to patients in the low PGSGA group, but not for the malnourished patients after neoadjuvant treatment. Using a 4NQO-induced tumor model, we found that nutrition supplementation decreased the rate of invasive tumor formation and attenuated the immune-suppressive microenvironment. In conclusion, malnutrition was associated with poor prognosis in esophageal-SCC patients. Nutritional status evaluated by PGSGA may be useful to guide treatment decisions in clinical practice. Nutritional supplementation is suggested to improve prognosis, and it might be related to augmented anticancer immune response.

Inhibition of NLRP3 inflammasome activation in myeloid-derived suppressor cells by andrographolide sulfonate contributes to 5-FU sensitization in mice.

5-Fluorouracil (5-FU)-based chemotherapy is the first-line recommended regimen in colorectal cancer (CRC), but resistance limits its clinical application. Andrographolide sulfonate, a traditional Chinese medicine, is mainly used to treat infectious diseases. In the present study, we reported that andrographolide sulfonate could significantly inhibit the growth of transplanted CT26 colon cancer in mice and improve survival when combined with 5-FU. Furthermore, TUNEL assay and immunohistochemistry analysis of proliferating cell nuclear antigen, Ki-67 and p-STAT3 confirmed that co-treatment could inhibit tumor proliferation and promote apoptosis. In tumor tissues of groups that received 5-FU and andrographolide sulfonate, CD4+ and CD8+ T cell infiltration was increased, and the expression of IFN-γ and Granzyme B detected by immunohistochemistry and qPCR was upregulated, reflecting improved antitumor immunity. Finally, we verified that 5-FU significantly activated the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome in myeloid-derived suppressor cells (MDSCs) and that andrographolide sulfonate reversed this process to sensitize cells to 5-FU. In summary, andrographolide sulfonate synergistically enhanced antitumor effects and improved antitumor immunity by inhibiting 5-FU-induced NLRP3 activation in MDSCs. These findings provide a novel strategy to address 5-FU resistance in the treatment of CRC.

Granulocytes and Cells of Granulocyte Origin-The Relevant Players in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common malignancy and cause of cancer death worldwide, and it still remains a therapeutic challenge for western medicine. There is strong evidence that, in addition to genetic predispositions, environmental factors have also a substantial impact in CRC development. The risk of CRC is attributed, among others to dietary habits, alcohol consumption, whereas physical activity, food containing dietary fiber, dairy products, and calcium supplements have a protective effect. Despite progress in the available therapies, surgery remains a basic treatment option for CRC. Implementation of additional methods of treatment such as chemo- and/or targeted immunotherapy, improved survival rates, however, the results are still far from satisfactory. One of the reasons may be the lack of deeper understanding of the interactions between the tumor and different types of cells, including tumor infiltrating granulocytes. While the role of neutrophils is quite well explored in many cancers, role of eosinophils and basophils is often underestimated. As part of this review, we focused on the function of different granulocyte subsets in CRC, emphasizing the beneficial role of eosinophils and basophils, as well as dichotomic mode of neutrophils action. In addition, we addressed the current knowledge on cells of granulocyte origin, specifically granulocytic myeloid derived suppressor cells (Gr-MDSCs) and their role in development and progression of CRC.

Acetylcholine ameliorates colitis by promoting IL-10 secretion of monocytic myeloid-derived suppressor cells through the nAChR/ERK pathway.

The alteration of the enteric nervous system (ENS) and its role in neuroimmune modulation remain obscure in the pathogenesis of inflammatory bowel diseases (IBDs). Here, by using the xCell tool and the latest immunolabeling-enabled three-dimensional (3D) imaging of solvent-cleared organs technique, we found severe pathological damage of the entire ENS and decreased expression of choline acetyltransferase (ChAT) in IBD patients. As a result, acetylcholine (ACh), a major neurotransmitter of the nervous system synthesized by ChAT, was greatly reduced in colon tissues of both IBD patients and colitis mice. Importantly, administration of ACh via enema remarkably ameliorated colitis, which was proved to be directly dependent on monocytic myeloid-derived suppressor cells (M-MDSCs). Furthermore, ACh was demonstrated to promote interleukin-10 secretion of M-MDSCs and suppress the inflammation through activating the nAChR/ERK pathway. The present data reveal that the cholinergic signaling pathway in the ENS is impaired during colitis and uncover an ACh-MDSCs neuroimmune regulatory pathway, which may offer promising therapeutic strategies for IBDs.

Comparing thermal stress reduction strategies that influence MDSC accumulation in tumor bearing mice.

Myeloid derived suppressor cells (MDSCs) are a diverse collection of immune cells that suppress anti-tumor immune responses. Decreasing MDSCs accumulation in the tumor microenvironment could improve the anti-tumor immune response and improve immunotherapy. Here, we examine the impact of physiologically relevant thermal treatments on the accumulation of MDSCs in tumors in mice. We found that different temperature-based protocols, including 1) weekly whole-body hyperthermia, 2) housing mice at their thermoneutral temperature (TT, ~30 °C), and 3) housing mice at a subthermoneutral temperature (ST,~22 °C) while providing a localized heat source, each resulted in a reduction in MDSC accumulation and improved tumor growth control compared to control mice housed at ST, which is the standard, mandated housing temperature for laboratory mice. Additionally, we found that low dose ß-adrenergic receptor blocker (propranolol) therapy reduced MDSC accumulation and improved tumor growth control to a similar degree as the models that relieved cold stress. These results show that thermal treatments can decrease MDSC accumulation and tumor growth comparable to propranolol therapy.

Effects of vitamin D on macrophages and myeloid-derived suppressor cells (MDSCs) hyperinflammatory response in the lungs of COVID-19 patients.

Vitamin D regulates homeostasis, anti-microbial response, and inflammation. The vitamin D receptors are expressed in the macrophages and other immune cells, regulating the transcription of many different genes, including those coding the anti-microbial peptides. One of the most severe complications of the SARS-CoV-2 infection is the acute respiratory distress syndrome (ARDS) caused by the hyperinflammatory response (commonly called cytokine storm) of the lung macrophages. Studies showed that Vitamin D deficiency increases the severity of the ARDS in COVID-19 infection. We discuss here how the vitamin D supplementation may influence macrophage and myeloid-derived suppressor cells (MDSCs) inflammatory response, subdue the hyperinflammatory response, and lessen the ARDS in COVID-19 patients.

Retinoic Acid Synthesis Deficiency Fosters the Generation of Polymorphonuclear Myeloid-Derived Suppressor Cells in Colorectal Cancer.

Metabolism is reprogrammed in cancer to fulfill the demands of malignant cells for cancer initiation and progression. Apart from its effects within cancer cells, little is known about whether and how reprogramed metabolism regulates the surrounding tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSC) are key regulators of the TME and greatly affect tumor progression and therapeutic responses. In this study, our results revealed that retinol metabolism-related genes and enzymes were significantly downregulated in human colorectal cancer compared with adjacent colonic tissues, and tumors exhibited a defect in retinoic acid (RA) synthesis. Reduced ADH1-mediated retinol metabolism was associated with attenuated RA signaling and accumulated MDSCs in colorectal cancer tumors. Using an in vitro model, generating MDSCs from CD34+ myeloid precursors, we found that exogenous RA could abrogate the generation of polymorphonuclear MDSCs (PMN-MDSC) with negligible impact on myeloid differentiation. Mechanistically, RA could restrain the glycolytic capacity of myeloid cells, which in turn activated the AMP-activated protein kinase (AMPK) pathway, further impairing the suppressive capacity of myeloid cells. Supplementation with RA could significantly delay tumor growth, with reduced arginase-1-expressing myeloid cells and increased CD8+ and granzyme B+ T cells in both colitis-associated and implanted MC38 mouse colorectal cancer models. Our results indicated that the defect in ADH1-mediated RA synthesis could provide a possible mechanism that fosters the generation of PMN-MDSCs in colorectal cancer and that restoring RA signaling in the TME could serve as a promising therapeutic strategy to abrogate the generation of PMN-MDSCs.

Myeloid Cells as Clinical Biomarkers for Immune Checkpoint Blockade.

Immune checkpoint inhibitors are becoming standard treatments in several cancer types, profoundly changing the prognosis of a fraction of patients. Currently, many efforts are being made to predict responders and to understand how to overcome resistance in non-responders. Given the crucial role of myeloid cells as modulators of T effector cell function in tumors, it is essential to understand their impact on the clinical outcome of immune checkpoint blockade and on the mechanisms of immune evasion. In this review we focus on the existing clinical evidence of the relation between the presence of myeloid cell subsets and the response to anti-PD(L)1 and anti-CTLA-4 treatment. We highlight how circulating and tumor-infiltrating myeloid populations can be used as predictive biomarkers for immune checkpoint inhibitors in different human cancers, both at baseline and on treatment. Moreover, we propose to follow the dynamics of myeloid cells during immunotherapy as pharmacodynamic biomarkers. Finally, we provide an overview of the current strategies tested in the clinic that use myeloid cell targeting together with immune checkpoint blockade with the aim of uncovering the most promising approaches for effective combinations.

Chinese herbal medicine Baoyuan Jiedu decoction inhibits the accumulation of myeloid derived suppressor cells in pre-metastatic niche of lung via TGF-ß/CCL9 pathway.

Baoyuan Jiedu (BYJD for short) decoction, a traditional Chinese medicine formula, is composed of Astragalus, Ginseng, Aconite root, Honeysuckle, Angelica, Licorice, which has the functions of nourishing qi and blood, enhancing immune function, improving quality of life and prolonging survival time of tumor patients. The present study aimed to investigate the effect and mechanism of BYJD decoction on reversing the pre-metastatic niche. We showed that BYJD decoction could prolong the survival time of 4T1 tumor-bearing mice. Moreover, we found that the BYJD decoction inhibited the formation of lung pre-metastatic niche and inhibited recruitment of myeloid derived suppressor cells (MDSCs) in the lung. Mechanistically, we showed that the proteins and genes expression of TGF-ß, Smad2, Smad3, p-Smad2/3, Smad4, CCL9 in the TGF-ß/CCL9 signaling pathway were suppressed by BYJD decoction. In line with the above findings, our results confirm that BYJD decoction inhibits the accumulation of MDSC in pre-metastatic niche of lung via TGF-ß/CCL9 pathway.

Supplementation of l-arginine boosts the therapeutic efficacy of anticancer chemoimmunotherapy.

Myeloid-derived suppressor cells (MDSCs) play a crucial role in immunosuppression in tumor-bearing hosts. MDSCs express arginase-I and indoleamine 2,3-dioxygenase; they suppress T-cell function by reducing the levels of l-arginine and l-tryptophan, respectively. We examined the anticancer effects of supplementation of these amino acids in CT26 colon carcinoma-bearing mice. Oral supplementation of l-arginine or l-tryptophan (30 mg/mouse) did not affect tumor growth, whereas oral supplementation of d-arginine was lethal. Supplementation of l-arginine showed a tendency to augment the efficacy of cyclophosphamide (CP). CP reduced the proportions of granulocytic MDSCs and increased the proportions of monocytic MDSCs in the spleen and tumor tissues of CT26-bearing mice. l-Arginine supplementation alone did not affect the MDSC subsets. CP treatment tended to reduce the plasma levels of l-arginine in CT26-bearing mice and significantly increased the number of tumor-infiltrating CD8+ T cells. In addition, l-arginine supplementation significantly increased the proportions of tumor peptide-specific CD8+ T cells in draining lymph nodes. Importantly, additional supplementation of l-arginine significantly increased the number of cured mice that were treated with CP and anti-PD-1 antibody. Totally, l-arginine supplementation shows promise for boosting the therapeutic efficacy of chemoimmunotherapy.

Green Tea Polyphenol EGCG Attenuates MDSCs-mediated Immunosuppression through Canonical and Non-Canonical Pathways in a 4T1 Murine Breast Cancer Model.

Several studies in the past decades have reported anti-tumor activity of the bioactive compounds extracted from tea leaves, with a focus on the compound epigallocatechin-3-gallate (EGCG). However, further investigations are required to unravel the underlying mechanisms behind the anti-tumor activity of EGCG. In this study, we demonstrate that EGCG significantly inhibits the growth of 4T1 breast cancer cells in vitro and in vivo. EGCG ameliorated immunosuppression by significantly decreasing the accumulation of myeloid-derived suppressor cells (MDSCs) and increasing the proportions of CD4+ and CD8+ T cells in spleen and tumor sites in 4T1 breast tumor-bearing mice. Surprisingly, a low dose of EGCG (0.5-5 µg/mL) effectively reduced the cell viability and increased the apoptosis rate of MDSCs in vitro. EGCG down-regulated the canonical pathways in MDSCs, mainly through the Arg-1/iNOS/Nox2/NF-κB/STAT3 signaling pathway. Moreover, transcriptomic analysis suggested that EGCG also affected the non-canonical pathways in MDSCs, such as ECM-receptor interaction and focal adhesion. qRT-PCR further validated that EGCG restored nine key genes in MDSCs, including Cxcl3, Vcan, Col4a1, Col8a1, Oasl2, Mmp12, Met, Itsnl and Acot1. Our results provide new insight into the mechanism of EGCG-associated key pathways/genes in MDSCs in the murine breast tumor model.