The Interactions of T Cells with Myeloid-Derived Suppressor Cells in Peripheral Blood Stem Cell Grafts.

The interaction of myeloid-derived suppressor cells (MDSCs) with T cells within G-CSF-mobilized peripheral blood stem cell (PBSC) grafts in patients undergoing autologous or allogeneic hematopoietic stem cell transplantation remains to be elucidated. Through studying allo- and auto-PBSC grafts, we observed grafts containing large numbers of T cells and MDSCs with intergraft variability in their percentage and number. T cells from autologous grafts compared to allografts expressed relative higher percentages of inhibitory receptors PD-1, CTLA-4, TIM-3, LAG-3, TIGIT and BTLA. Autograft T cells had decreased cell proliferation and IFN-γ secretion, which supported the possible presence of T cell exhaustion. On the contrary, graft monocytic MDSCs (M-MDSCs) expressed multiple inhibitory receptor ligands, including PD-L1, CD86, Galectin-9, HVEM and CD155. The expression of inhibitory receptor ligands on M-MDSCs was correlated with their corresponding inhibitory receptors on T cells in the grafts. Isolated M-MDSCs had the ability to suppress T cell proliferation and IFN-γ secretion and/or promote Treg expansion. Blocking the PD-L1-PD-1 signaling pathway partially reversed the functions of M-MDSCs. Taken together, our data indicated that T cells and M-MDSCs in PBSC grafts express complementary inhibitory receptor-ligand pairing, which may impact the quality of immune recovery and clinical outcome post transplantation.

Role of Nutrients Regulating Myeloid Derived Suppressor Cells in Cancer: A Scoping Review.

Myeloid-derived suppressor cells (MDSCs) are immature cells with an immunosuppressive function. MDSCs have been related to inflammation in many settings, including infections, transplantation, obesity, aging, or cancer. In oncological settings, MDSCs participate in tumor immunoescape, growth, and metastasis. Certain nutrients can modify chronic inflammation by their interaction with MDSCs. Therefore, the possible influence of certain nutrients on immune surveillance by their actions on MDSCs and how this may affect the prognosis of cancer patients were evaluated in this scoping review. We identified seven papers, six of which were murine model studies and only one was a human clinical trial. Globally, a significant reduction in cancer growth and progression was observed after achieving a reduction in both MDSCs and their immunosuppressive ability with nutrients such as selected vegetables, icaritin, retinoic acid, curdlan, active vitamin D, soy isoflavones, and green tea. In conclusion, the consumption of certain nutrients may have effects on MDSCs, with beneficial results not only in the prevention of tumor development and growth but also in improving patients' response.

Myeloid-derived suppressor cells alleviate adverse ventricular remodeling after acute myocardial infarction.

The fundamental pathophysiological mechanism in the progression of chronic heart failure following acute myocardial infarction (AMI) is ventricular remodeling, in which innate and adaptive immunity both play critical roles. Myeloid-derived suppressor cells (MDSCs) have been demonstrated to function in a range of pathological conditions, such as infections, inflammation, autoimmune diseases, and tumors. However, it is unclear how MDSCs contribute to cardiac remodeling following AMI. This study aimed to identify the function and underlying mechanism of MDSCs in controlling cardiac remodeling following AMI. Following AMI in mice, MDSCs frequencies changed dynamically, considerably increased on day 7 in blood, spleens, lymph nodes and hearts, and decreased afterwards. Consistently, mice with AMI displayed enhanced cardiac function on day 14 post-AMI, reduced infract size and higher survival rates on day 28 post-AMI following the adoptive transfer of MDSCs. Furthermore, MDSCs inhibited the inflammatory response by decreasing pro-inflammatory cytokine (TNF-α, IL-17, Cxcl-1, and Cxcl-2) expression, up-regulating anti-inflammatory cytokine (TGF-ß1, IL-10, IL-4, and IL-13) expression, reducing CD3+ T cell infiltration in the infarcted heart and enhancing M2 macrophage polarization. Mechanistically, MDSCs improved the release of anti-inflammatory factors (TGF-ß1 and IL-10) and decreased the injury of LPS-induced cardiomyocytes in vitro in a manner dependent on cell-cell contact. Importantly, blockade of IL-10 partially abolished the cardioprotective role of MDSCs. This study found that MDSCs contributed to the restoration of cardiac function and alleviation of adverse cardiac remodeling after AMI possibly by inhibiting inflammation.

Myeloid-derived suppressor cells in cancer: Current knowledge and future perspectives.

MDSCs (myeloid-derived suppressor cells) are crucial for immune system evasion in cancer. They accumulate in peripheral blood and tumor microenvironment, suppressing immune cells like T-cells, natural killer cells and dendritic cells. They promote tumor angiogenesis and metastasis by secreting cytokines and growth factors and contribute to a tumor-promoting environment. The accumulation of MDSCs in cancer patients has been linked to poor prognosis and resistance to various cancer therapies. Targeting MDSCs and their immunosuppressive mechanisms may improve treatment outcomes and enhance immune surveillance by developing drugs that inhibit MDSC function, by preventing their accumulation and by disrupting the tumor-promoting environment. This review presents a detailed overview of the MDSC research in cancer with regulation of their development and function. The relevance of MDSC as a prognostic and predictive biomarker in different types of cancers, along with recent advancements on the therapeutic approaches to target MDSCs are discussed in detail.

Impact of Microparticle Transarterial Chemoembolization (mTACE) on myeloid-derived suppressor cell subtypes in hepatocellular carcinoma: Clinical correlations and therapeutic implications.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) play a pivotal role in immunosuppression and tumor progression in hepatocellular carcinoma (HCC). While various treatments like surgical resection, ablation, and radiotherapy have been studied for their effects on circulating MDSC frequencies in HCC patients, the findings remain inconclusive. Transarterial Chemoembolization (TACE) stands as the standard care for unresectable HCC, with Microparticle TACE (mTACE) gaining prominence for its capacity to induce significant tumor necrosis. However, the immunological ramifications of such pathological outcomes are scarcely reported. METHODS AND RESULTS: This study aims to elucidate the alterations in MDSC subtypes, specifically monocytic MDSCs (mMDSCs) and early-stage MDSCs (eMDSCs), post-mTACE and to investigate their clinical correlations in HCC patients. A cohort comprising 75 HCC patients, 16 liver cirrhosis patients, and 20 healthy controls (HC) was studied. Peripheral blood samples were collected and analyzed for MDSC subtypes. The study also explored the associations between MDSC frequencies and various clinical parameters in HCC patients. The frequency of mMDSCs was significantly elevated in the HCC group compared to liver cirrhosis and HC. Importantly, mMDSC levels were strongly correlated with aggressive clinical features of HCC, including tumor size, vascular invasion, and distant metastasis. Post-mTACE, a marked reduction in mMDSC frequencies was observed, while eMDSC levels remained stable. CONCLUSIONS: Our findings underscore the critical role of mMDSCs in HCC pathogenesis and their potential as a therapeutic target. The study also highlights the efficacy of mTACE in modulating the immunosuppressive tumor microenvironment, thereby opening new avenues for combinatorial immunotherapeutic strategies in HCC management.

Dual Oxygen-Supply Immunosuppression-Inhibiting Nanomedicine to Avoid the Intratumoral Recruitment of Myeloid-Derived Suppressor Cells.

Myeloid-derived suppressor cells (MDSCs) are reported to be responsible for the negative prognosis of colorectal cancer (CRC) patients due to the mediated immunosuppressive tumor microenvironment (TME). The selective and chronic circumvention of tumor-infiltrated MDSCs has potential clinical significance for CRC treatment, which unluckily remains a technical challenge. Because tumor hypoxia makes a significant contribution to the recruitment of MDSCs in tumor sites, a dual oxygen-supplied immunosuppression-inhibiting nanomedicine (DOIN) is demonstrated for overcoming tumor hypoxia, which achieves selective and long-term inhibition of intratumoral recruitment of MDSCs. The DOIN is constructed by the encasement of perfluorooctyl bromide (PFOB) and 4-methylumbelliferone (4-MU) into a TME-responsive amphiphilic polymer. This nanoplatform directly carries oxygen to the tumor region and simultaneously loosens the condensed tumor extracellular matrix for the normalization of tumor vasculature, which selectively remodels the TME toward one adverse to the intratumoral recruitment of MDSCs. Importantly, this nanoplatform offers a long-acting alleviation of the hypoxic TME, chronically avoiding the comeback of tumor-infiltrated MDSCs. Consequently, the immunosuppressive TME is relieved, and T cells are successfully proliferated and activated into cytotoxic T lymphocytes, which boosts a systemic immune response and contributes to lasting inhibition of tumor growth with a prolonged survival span of xenograft.

Epigenetic control of immunoevasion in cancer stem cells.

Cancer stem cells (CSCs) are a poorly differentiated population of malignant cells that (at least in some neoplasms) is responsible for tumor progression, resistance to therapy, and disease relapse. According to a widely accepted model, all stages of cancer progression involve the ability of neoplastic cells to evade recognition or elimination by the host immune system. In line with this notion, CSCs are not only able to cope with environmental and therapy-elicited stress better than their more differentiated counterparts but also appear to better evade tumor-targeting immune responses. We summarize epigenetic modifications of DNA and histones through which CSCs evade immune recognition or elimination, and propose that such alterations constitute promising therapeutic targets to increase the sensitivity of some malignancies to immunotherapy.

Multiplex spatial analysis reveals increased CD137 expression and m-MDSC neighboring tumor cells in refractory classical Hodgkin Lymphoma.

The Hodgkin and Reed - Sternberg (HRS) cells in classical Hodgkin Lymphoma (cHL) actively modify the immune tumor microenvironment (TME) attracting immunosuppressive cells and expressing inhibitory molecules. A high frequency of myeloid cells in the TME is correlated with an unfavorable prognosis, but more specific and rare cell populations lack precise markers. Myeloid-derived suppressor cells (MDSCs) have been identified in the peripheral blood of cHL patients, where they appear to be correlated with disease aggressiveness. TNFRSF9 (CD137) is a T cell co-stimulator expressed by monocytic and dendritic cells. Its expression has also been described in HRS cells, where it is thought to play a role in reducing antitumor responses. Here, we perform qualitative and quantitative analyses of lymphocytic and MDSC subtypes and determine the CD137 cell distribution in cHL primary tumors using multiplex immunofluorescence and automated multispectral imaging. The results were correlated with patients' clinical features. Cells were stained with specific panels of immune checkpoint markers (PD-1, PD-L1, CD137), tumor-infiltrating T lymphocytes (CD3, PD-1), and monocytic cells/MDSCs (CD68, CD14, CD33, Arg-1, CD11b). This approach allowed us to identify distinct phenotypes and to analyze spatial interactions between immune subpopulations and tumor cells. The results confirm CD137 expression by T, monocytic and HRS cells. In addition, the expression of CD137, T exhausted cells, and monocytic MDSCs (m-MDSCs) in the vicinity of malignant HRS cells were associated with a worse prognosis. Our findings reveal new elements of the TME that mediate immune escape, and confirm CD137 as a candidate target for immunotherapy in cHL.

CD137-expressing immune cells and HRS cells are more abundant and in closer proximity in refractory patients than in responders.Monocytic myeloid-derived suppressor cells (m-MDSCs) are associated with unfavorable outcomes and relapse in cHL, unlike granulocytic MDSCs (g-MDSCs), which are located far from HRS cells in non-responders.The cHL tumor microenvironment promotes immune escape in refractory patients by holistically driving polarization and/or recruitment of several cell types with increased expression of CD137 and PD-L1 checkpoints.

5-Fluorouracil resistance due to sphingosine kinase 2 overexpression in colorectal cancer is associated with myeloid-derived suppressor cell-mediated immunosuppressive effects.

PURPOSE: Colorectal cancer (CRC) is one of the top five cancer-related causes of mortality globally. Acquired resistance has hindered the effectiveness of 5-fluorouracil (5-FU), the main chemotherapeutic drug used to treat CRC. Sphingosine kinase 2 (SphK2) may be a cancer treatment target and involved in 5-FU resistance. METHODS: Cell growth was examined using MTT and clone formation assays for SphK2 expression. To identify immune cells in mice, flow cytometry was performed. West blotting demonstrated alterations in cell division and inflammation-related proteins. SphK2 levels and inflammation-related variables were studied using Elisa. RESULTS: Due to SphK2 overexpression, immunosuppression, and 5-FU resistance are caused by the development of myeloid-derived suppressor cells (MDSCs) subsequent to IL-6/STAT3 activation and alterations in the arginase (ARG-1) protein. After therapy, the combination of SphK2 inhibitors and 5-FU can effectively suppress MDSCs while increasing CD4+ and CD8+ T cell infiltration into the tumor microenvironment, lowering tumor burden, and exhibiting a therapeutic impact on CRC. CONCLUSIONS: Our findings suggest that 5-FU treatment combined with simultaneous Spkh2 inhibition by ABC294640 has anti-tumor synergistic effects by influencing multiple effects on tumor cells, T cells, and MDSCs, potentially improving the poor prognosis of colorectal cancer patients.

Tumor-derived GLI1 promotes remodeling of the immune tumor microenvironment in melanoma.

BACKGROUND: Melanoma progression is based on a close interaction between cancer cells and immune cells in the tumor microenvironment (TME). Thus, a better understanding of the mechanisms controlling TME dynamics and composition will help improve the management of this dismal disease. Work from our and other groups has reported the requirement of an active Hedgehog-GLI (HH-GLI) signaling for melanoma growth and stemness. However, the role of the downstream GLI1 transcription factor in melanoma TME remains largely unexplored. METHODS: The immune-modulatory activity of GLI1 was evaluated in a syngeneic B16F10 melanoma mouse model assessing immune populations by flow cytometry. Murine polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were differentiated from bone marrow cells and their immunosuppressive ability was assessed by inhibition of T cells. Conditioned media (CM) from GLI1-overexpressing mouse melanoma cells was used to culture PMN-MDSCs, and the effects of CM were evaluated by Transwell invasion assay and T cell inhibition. Cytokine array analysis, qPCR and chromatin immunoprecipitation were performed to explore the regulation of CX3CL1 expression by GLI1. Human monocyte-derived dendritic cells (moDCs) were cultured in CM from GLI1-silenced patient-derived melanoma cells to assess their activation and recruitment. Blocking antibodies anti-CX3CL1, anti-CCL7 and anti-CXCL8 were used for in vitro functional assays. RESULTS: Melanoma cell-intrinsic activation of GLI1 promotes changes in the infiltration of immune cells, leading to accumulation of immunosuppressive PMN-MDSCs and regulatory T cells, and to decreased infiltration of dendric cells (DCs), CD8 + and CD4 + T cells in the TME. In addition, we show that ectopic expression of GLI1 in melanoma cells enables PMN-MDSC expansion and recruitment, and increases their ability to inhibit T cells. The chemokine CX3CL1, a direct transcriptional target of GLI1, contributes to PMN-MDSC expansion and recruitment. Finally, silencing of GLI1 in patient-derived melanoma cells promotes the activation of human monocyte-derived dendritic cells (moDCs), increasing cytoskeleton remodeling and invasion ability. This phenotype is partially prevented by blocking the chemokine CCL7, but not CXCL8. CONCLUSION: Our findings highlight the relevance of tumor-derived GLI1 in promoting an immune-suppressive TME, which allows melanoma cells to evade the immune system, and pave the way for the design of new combination treatments targeting GLI1.

γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner.

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.

Targeting myeloid-derived suppressor cells by inhibiting hypoxia-inducible factor 1α could improve tumor progression.

Myeloid-derived suppressor cells (MDSCs) are a subset of immature myeloid cells that inhibit anti-tumor immunity and contribute to poor cancer outcomes. In this study, the authors used multi-color flow cytometry to detect changes in MDSCs in patients with cancer and tumor-bearing mice. Then the authors studied changes in MDSCs ratio and mouse tumors after administration of hypoxia-inducible factor 1α (HIF-1α) inhibitor. The results showed that the ratio of MDSCs, specifically polymorphonuclear MDSCs (PMN-MDSCs), was higher in patients with cancer, and both PMN-MDSCs and monocytic MDSCs (M-MDSCs) ratio were higher in tumor-bearing mice. When provided with the HIF-1α inhibitor LW-6, the ratio of MDSCs decreased in tumor-bearing mice, particularly PMN-MDSCs, and the volume of liver metastases also decreased. The authors' findings suggest that reducing MDSCs by inhibiting hypoxia-inducible factor 1α may slow tumor progression.

MDSCs promote pathological angiogenesis in ocular neovascular disease.

BACKGROUND: Ocular neovascular diseases, which contribute significantly to vision loss, lack effective preventive treatments. Recent studies have highlighted the significant involvement of immune cells in neovascular retinopathy. Myeloid-derived suppressor cells (MDSCs) promote the development of neovascularization, but it is unknown whether they participate in pathological neovascularization and whether they are expected to be a therapeutic target. METHOD: We investigated the role of MDSCs in promoting pathological angiogenesis using an oxygen-induced retinopathy (OIR) model, employing flow cytometry, immunofluorescence, and smart-seq analysis. Then, we evaluated the proportion of MDSCs in patient blood samples using flow cytometry. Additionally, we assessed the effect of MDSC depletion using an anti-Gr-1 monoclonal antibody on retinal vasculopathy and alterations in retinal microglia. RESULTS: In the OIR model, an elevated ratio of MDSCs was observed in both blood and retinal tissue during phase II (Neovascularization). The depletion of MDSCs resulted in reduced retinal neovascularization and vaso-obliteration, along with a decrease in microglia within the neovascularization area. Furthermore, analysis of gene transcripts associated with MDSCs indicated activation of vascular endothelial growth factor (VEGF) regulation and inflammation. Importantly, infants with ROP exhibited a higher proportion of MDSCs in their blood samples. CONCLUSION: Our results suggested that excessive MDSCs represent an unrecognized feature of ocular neovascular diseases and be responsible for the retinal vascular inflammation and angiogenesis, providing opportunities for new therapeutic approaches to ocular neovascular disease.

Crucial role of dendritic cells in the generation of anti-tumor T-cell responses and immunogenic tumor microenvironment to suppress tumor development.

Dendritic cells (DCs) are known as unique professional antigen (Ag)-presenting cells (APCs) to prime naïve T cells for the initiation of adaptive immunity. While DCs are believed to play a pivotal role in generating anti-tumor T-cell responses, the importance of DCs in the protection from the progression of tumors remains elusive. Here, we show how the constitutive deficiency of CD11chi DCs influences the progression of tumors with the use of binary transgenic mice with constitutive loss of CD11chi DCs. Constitutive loss of CD11chi DCs not only enhances the progression of tumors but also reduces the responses of Ag-specific T cells. Furthermore, the congenital deficiency of CD11chi DCs generates the immunosuppressive tumor microenvironment (TME) that correlates with the marked accumulation of myeloid-derived suppressor cells (MDSCs) and the prominent productions of immunosuppressive mediators. Thus, our findings suggest that CD11chi DCs are crucial for generating anti-tumor T-cell responses and immunogenic TME to suppress the development of tumors.

Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment.

Pancreatic cancer demonstrates an ever-increasing incidence over the last years and represents one of the top causes of cancer-associated mortality. Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells' metabolism, inhibit drug delivery, enhance immune suppression mechanisms and finally develop resistance to chemotherapy and immunotherapy. New strategies target TME genetic alterations and specific pathways in cell populations of the TME. Complex molecular interactions develop between PDAC cells and TME cell populations including cancer-associated fibroblasts, myeloid-derived suppressor cells, pancreatic stellate cells, tumor-associated macrophages, tumor-associated neutrophils, and regulatory T cells. In the present review, we aim to fully explore the molecular landscape of the pancreatic cancer TME cell populations and discuss current TME targeting strategies to provide thoughts for further research and preclinical testing.

Factors Affecting an Increase in Spleen Volume and Association of Spleen Volume Variation with the Clinical Outcomes of Atezolizumab and Bevacizumab Treatment for Hepatocellular Carcinoma: A Retrospective Analysis.

INTRODUCTION: Gastrointestinal varices rupture is considered to be prone to occur during atezolizumab and bevacizumab (Atez/Bev) treatment. This study aimed to investigate predictive factors affecting the increase in spleen volume (SpV) and the association of SpV variation with the clinical outcomes of Atez/Bev. METHODS: A total of 164 HCC patients were included in this retrospective multicenter study. We measured SpV based on CT scans obtained before treatment and at evaluations. We used the inverse probability of treatment weight to address the imbalance between patient characteristics. RESULTS: The median pretreatment SpV was 184 (130-257) cm3 and the median SpV variation was 27 (9-60) cm3. An increase in the SpV was observed in 140 patients (85.4%). Age <74 years (p = 0.03), mALBI grade 2b or 3 (p = 0.03), and pretreatment SpV ≥184 cm3 (p < 0.001) were significantly associated with increased SpV. There were no significant differences in progression-free survival (PFS) or overall survival (OS) between patients with SpV variation <25 cm3 and those with SpV variation ≥25 cm3 in the crude (p = 0.3 and 0.7) and IPTW-weighted cohorts (p = 0.08 and 0.8, respectively). Regarding pretreatment SpV, there were no significant differences in PFS or OS between patients with and without pretreatment spleen enlargement in the crude (both p = 0.3) and IPTW-weighted cohort (p = 0.6 and 0.3, respectively). CONCLUSION: Caution is warranted to detect the aggravation of portal hypertension when administering Atez/Bev to young patients or patients with an impaired liver function or pretreatment spleen enlargement. The impact of spleen modulation by Atez/Bev appears to be limited on clinical efficacy.

Targeting CSF1R in myeloid-derived suppressor cells: insights into its immunomodulatory functions in colorectal cancer and therapeutic implications.

OBJECTIVE: This study aimed to investigate the critical role of MDSCs in CRC immune suppression, focusing on the CSF1R and JAK/STAT3 signaling axis. Additionally, it assessed the therapeutic efficacy of LNCs@CSF1R siRNA and anti-PD-1 in combination. METHODS: Single-cell transcriptome sequencing data from CRC and adjacent normal tissues identified MDSC-related differentially expressed genes. RNA-seq analysis comprehensively profiled MDSC gene expression in murine CRC tumors. LNCs@CSF1R siRNA nanocarriers effectively targeted and inhibited CSF1R. Flow cytometry quantified changes in MDSC surface markers post-CSF1R inhibition. RNA-seq and pathway enrichment analyses revealed the impact of CSF1R on MDSC metabolism and signaling. The effect of CSF1R inhibition on the JAK/STAT3 signaling axis was validated using Colivelin and metabolic assessments. Glucose and fatty acid uptake were measured via fluorescence-based flow cytometry. The efficacy of LNCs@CSF1R siRNA and anti-PD-1, alone and in combination, was evaluated in a murine CRC model with extensive tumor section analyses. RESULTS: CSF1R played a significant role in MDSC-mediated immune suppression. LNCs@CSF1R siRNA nanocarriers effectively targeted MDSCs and inhibited CSF1R. CSF1R regulated MDSC fatty acid metabolism and immune suppression through the JAK/STAT3 signaling axis. Inhibition of CSF1R reduced STAT3 activation and target gene expression, which was rescued by Colivelin. Combined treatment with LNCs@CSF1R siRNA and anti-PD-1 significantly slowed tumor growth and reduced MDSC abundance within CRC tumors. CONCLUSION: CSF1R via the JAK/STAT3 axis critically regulates MDSCs, particularly in fatty acid metabolism and immune suppression. Combined therapy with LNCs@CSF1R siRNA and anti-PD-1 enhances therapeutic efficacy in a murine CRC model, providing a strong foundation for future clinical applications.

Myeloid-derived Suppressor Cells and Multiple Sclerosis.

Myeloid-Derived Suppressor Cells (MDSCs) are a heterogeneous population of immature myeloid cells that play important roles in maintaining immune homeostasis and regulating immune responses. MDSCs can be divided into two main subsets based on their surface markers and functional properties: granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs). Recently greatest attention has been paid to innate immunity in Multiple Sclerosis (MS), so the aim of our review is to provide an overview of the main characteristics of MDSCs in MS and its preclinical model by discussing the most recent data available. The immunosuppressive functions of MDSCs can be dysregulated in MS, leading to an exacerbation of the autoimmune response and disease progression. Antigen-specific peptide immunotherapy, which aims to restore tolerance while avoiding the use of non-specific immunosuppressive drugs, is a promising approach for autoimmune diseases, but the cellular mechanisms behind successful therapy remain poorly understood. Therefore, targeting MDSCs could be a promising therapeutic approach for MS. Various strategies for modulating MDSCs have been investigated, including the use of pharmacological agents, biological agents, and adoptive transfer of exogenous MDSCs. However, it remained unclear whether MDSCs display any therapeutic potential in MS and how this therapy could modulate different aspects of the disease. Collectively, all the described studies revealed a pivotal role for MDSCs in the regulation of MS.

Non-Coding RNA in Tumor Cells and Tumor-Associated Myeloid Cells-Function and Therapeutic Potential.

The RNA world is wide, and besides mRNA, there is a variety of other RNA types, such as non-coding (nc)RNAs, which harbor various intracellular regulatory functions. This review focuses on small interfering (si)RNA and micro (mi)RNA, which form a complex network regulating mRNA translation and, consequently, gene expression. In fact, these RNAs are critically involved in the function and phenotype of all cells in the human body, including malignant cells. In cancer, the two main targets for therapy are dysregulated cancer cells and dysfunctional immune cells. To exploit the potential of mi- or siRNA therapeutics in cancer therapy, a profound understanding of the regulatory mechanisms of RNAs and following targeted intervention is needed to re-program cancer cells and immune cell functions in vivo. The first part focuses on the function of less well-known RNAs, including siRNA and miRNA, and presents RNA-based technologies. In the second part, the therapeutic potential of these technologies in treating cancer is discussed, with particular attention on manipulating tumor-associated immune cells, especially tumor-associated myeloid cells.

Interleukin-1 receptor 1 deficiency worsens hepatocellular carcinoma, while gemcitabine treatment alleviates the hepatocellular carcinoma-induced increase in intra-hepatic immune cells.

BACKGROUND AND AIM: Primary liver cancer, particularly hepatocellular carcinoma (HCC), represents a substantial global health challenge. Although immune checkpoint inhibitors are effective in HCC treatment, several patients still experience disease progression. Interleukin-1 (IL-1) regulates immunity and inflammation. We investigate the role of IL-1 in HCC development and progression and determine the potential therapeutic impact of gemcitabine in treating HCC. METHODS: Hydrodynamics-based transfection, employing the sleeping beauty transposase system, delivered surrogate tumor antigens, NRAS (NRAS proto-oncogene, GTPase), ShP53, and SB100 to C57BL/6 mice. A basic HCC mouse model was established. Pathogen-free animals were tested for serum and hepatotoxicity. The HCC prognosis was monitored using alanine aminotransferase and aspartate aminotransferase levels. Liver histology immunohistochemistry and mouse splenocyte/intra-hepatic immune cell flow cytometry were conducted. IL-1ß levels in human and mouse serum were assessed. RESULTS: Interleukin-1ß levels were elevated in patients with HCC compared with those in non-HCC controls. Hepatic IL-1ß levels were higher in HCC mouse models than those in non-HCC mice, suggesting localized hepatic inflammation. IL-1 receptor type 1 (IL-1R1) knockout (IL-1R1-/-) mice exhibited less severe HCC progression than that in wild-type mice, despite the high intra-hepatic IL-1ß concentration. IL-1R1-/- mice exhibited increased hepatic levels of myeloid-derived suppressor cells and regulatory T cells, which may exacerbate HCC. Gemcitabine significantly reduced the HCC tumor burden, improved liver conditions, and increased survival rates in HCC mouse models. Gemcitabine reduced the hepatic levels of myeloid-derived suppressor cells and regulatory T cells, potentially alleviating immune suppression in the liver. CONCLUSIONS: Targeting IL-1 or combining gemcitabine with immunotherapy is a promising approach for treating advanced-stage HCC.