Generation Of Suppressor Cells Research Articles

Host ANGPTL2 establishes an immunosuppressive tumor microenvironment and resistance to immune checkpoint therapy.

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor "immunophenotypes" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness.

Peripheral-derived regulatory T cells contribute to tumor-mediated immune suppression in a nonredundant manner

Identifying tumor-mediated mechanisms that impair immunity is instrumental for the design of new cancer therapies. Regulatory T cells (Tregs) are a key component of cancer-derived immune suppression; however, these lymphocytes are necessary to prevent systemic autoimmunity in mice and humans, and thus, direct targeting of Tregs is not a clinical option for cancer patients. We have previously demonstrated that excising transcription factor Kruppel-like factor 2 (Klf2) within the T cell lineage blocks the generation of peripheral-derived Tregs (pTregs) without impairing production of thymic-derived Tregs. Using this mouse model, we have now demonstrated that eliminating pTregs is sufficient to delay/prevent tumor malignancy without causing autoimmunity. Cancer-bearing mice that expressed KLF2 converted tumor-specific CD4+ T cells into pTregs, which accumulated in secondary lymphoid organs and impaired further T cell effector activity. In contrast, pTreg-deficient mice retained cancer-specific immunity, including improved T cell infiltration into "cold" tumors, reduced T cell exhaustion in tumor beds, restricted generation of tumor-associated myeloid-derived suppressor cells, and the continued production of circulating effector T cells that arose in a cancer-dependent manner. Results indicate that tumor-specific pTregs are critical for early stages of cancer progression and blocking the generation of these inhibitory lymphocytes safely delays/prevents malignancy in preclinical models of melanoma and prostate cancer.

Generation of Myeloid-Derived Suppressor Cells Mediated by MicroRNA-125a-5p in Melanoma.

The ability of tumor-derived extracellular vesicles (EVs) to modulate the function of myeloid cells is widely recognized. Hence, a comprehensive understanding of the distinct components associated with EVs and the signals that they deliver to myeloid cells could provide potential approaches to impede the immunosuppression by myeloid-derived suppressor cells (MDSCs). We investigated melanoma EV-associated microRNAs (miRs) using the RET transgenic melanoma mouse model and simulated their transfer to normal myeloid cells by transfecting immature mouse myeloid cells and human monocytes. We observed elevated levels of miR-125a-5p, -125b-5p, and let-7e-5p in mouse melanoma-infiltrating MDSCs. In addition, miR-125a-5p levels in the tumor microenvironment correlated with mouse melanoma progression. The delivery of miR-125a-5p, alone or in combination with let-7e-5p and miR-99b-5p from the same genomic cluster, to normal myeloid cells resulted in their conversion to MDSC-like cells. Our findings indicate that miR-125a-5p could modulate myeloid cell activation in the melanoma microenvironment via a NF-κB-dependent mechanism.

Interleukin-27 Promotes the Generation of Myeloid-derived Suppressor Cells to Alleviate Graft-versus-host Disease.

Stimulation of myeloid-derived suppressor cell (MDSC) formation represents a potential curative therapeutic approach for graft-versus-host disease (GVHD), which significantly impacts the prognosis of allogeneic hematopoietic stem cell transplantation. However, the lack of an effective strategy for inducing MDSC production in vivo has hindered their clinical application. In our previous study, MDSC expansion was observed in interleukin (IL)-27-treated mice. In this study, we overexpressed exogenous IL-27 in mice using a recombinant adeno-associated virus vector to investigate its therapeutic and exacerbating effects in murine GVHD models. In our study, we demonstrated that exogenous administration of IL-27 significantly suppressed GVHD development in a mouse model. We found that IL-27 treatment indirectly inhibited the proliferation and activation of donor T cells by rapidly expanding recipient and donor myeloid cells, which act as MDSCs after irradiation or under inflammatory conditions, rather than through regulatory T-cell expansion. Additionally, IL-27 stimulated MDSC expansion by enhancing granulocyte-monocyte progenitor generation. Notably, we verified that IL-27 signaling in donor T cells exerted an antagonistic effect on GVHD prevention and treatment. Further investigation revealed that combination therapy involving IL-27 and T-cell depletion exhibited remarkable preventive effects on GVHD in both mouse and xenogeneic GVHD models. Collectively, these findings suggest that IL-27 promotes MDSC generation to reduce the incidence of GVHD, whereas targeted activation of IL-27 signaling in myeloid progenitors or its combination with T-cell depletion represents a potential strategy for GVHD therapy.

In vitro generation of murine myeloid-derived suppressor cells from hematopoietic progenitor cells.

One of the hallmarks of cancer is the expansion and accumulation of highly immunosuppressive myeloid cells known as myeloid-derived suppressor cells (MDSCs). To study MDSCs biology, differentiation from hematopoietic progenitor cells (HPC) is an useful tool to elucidate the biological and biochemical mechanisms associated with acquisition of immune suppressive activity and expansion in cancer. Although this is one of the protocols performed to study immune suppressive myeloid cells, differentiation of MDSCs from HPC is a method that allows to modify conditions of the supernatants used. In this protocol, we outline the process of differentiating HPCs into MDSCs in vitro using tumor explant supernatants to recapitulate the tumor microenvironment.

Chronic social defeat stress-induced depression reduces BCG efficacy by promoting regulatory T-cell levels in mice

Despite the initial successes of the Bacillus Calmette-Guerin (BCG) vaccine in children, its efficacy against tuberculosis is highly variable. There is a lack of understanding about how mental conditions influence BCG vaccination. Here, we used the chronic social defeat stress (CSDS) model to explore the effects of depression on BCG vaccination efficacy. We observed higher lung and spleen bacterial loads and a lower organ index in depressed compared to BCG mice. Meanwhile, a relatively lower T cell protective efficacy was observed in both compared to control and BCG mice via a mycobacterium growth inhibition assay (MGIA). Cytokine expression of IL-12p40, IL-1β, IL-17, TNF-α and IFN-γ was reduced, whereas the expression of IL-10 and IL-5 was increased in the spleen of both compared to BCG mice. Moreover, the proportions of CD4+IFN-γ+, CD8+IFN-γ+ T lymphocytes and CD4+ effector/central memory T cells were reduced in the splenocytes of the depressed BCG mice. Depression promotes CD4+ regulatory T cells (Treg) and myeloid-derived suppressor cell (MDSC) generation in depressed mice, contributing to the reduced pro-inflammatory immune response upon BCG vaccination. This study provides insight into the decreased protective immunity by BCG vaccination attributable to depression in mice.

Short-term immune-checkpoint inhibition partially rescues perturbed bone marrow hematopoiesis in mismatch-repair deficient tumors

ABSTRACT Wide-spread cancer-related immunosuppression often curtails immune-mediated antitumoral responses. Immune-checkpoint inhibitors (ICIs) have become a state-of-the-art treatment modality for mismatch repair-deficient (dMMR) tumors. Still, the impact of ICI-treatment on bone marrow perturbations is largely unknown. Using anti-PD1 and anti-LAG-3 ICI treatments, we here investigated the effect of bone marrow hematopoiesis in tumor-bearing Msh2loxP/loxP;TgTg(Vil1- cre) mice. The OS under anti-PD1 antibody treatment was 7.0 weeks (vs. 3.3 weeks and 5.0 weeks, control and isotype, respectively). In the anti-LAG-3 antibody group, OS was 13.3 weeks and thus even longer than in the anti-PD1 group (p = 0.13). Both ICIs induced a stable disease and reduced circulating and splenic regulatory T cells. In the bone marrow, a perturbed hematopoiesis was identified in tumor-bearing control mice, which was partially rescued by ICI treatment. In particular, B cell precursors and innate lymphoid progenitors were significantly increased upon anti-LAG-3 therapy to levels seen in tumor-free control mice. Additional normalizing effects of ICI treatment were observed for lin−c-Kit+IRF8+ hematopoietic stem cells, which function as a “master” negative regulator of the formation of polymorphonuclear-myeloid-derived suppressor cell generation. Accompanying immunofluorescence on the TME revealed significantly reduced numbers of CD206+F4/80+ and CD163+ tumor-associated M2 macrophages and CD11b+Gr1+ myeloid-derived suppressor cells especially upon anti-LAG-3 treatment. This study confirms the perturbed hematopoiesis in solid cancer. Anti-LAG-3 treatment partially restores normal hematopoiesis. The interference of anti-LAG-3 with suppressor cell populations in otherwise inaccessible niches renders this ICI very promising for subsequent clinical application.

At Once Friends and Foes

Mycobacterium tuberculosis (Mtb) is the causative agent of human tuberculosis (TB) disease. In chronic infections such as TB, consistent pro-inflammatory signalling promotes the generation of myeloid-derived suppressor cells (MDSCs). MDSCs are innate immune cells that are further divided into polymorphonuclear (PMN-MDSC) and monocytic (M-MDSC) subtypes on the basis of their morphology. These cells exert immunosuppressive effects on other immune cell types, thereby protecting the integrity of the lung tissue from damage caused by dysregulated Mtb. However, this comes at the expense of containing the Mtb infection. MDSCs’ unique double-edged role makes them an attractive target for host-directed TB therapeutics. This review aims to summarize current knowledge on the role of MDSCs in TB.

Nicotinamide N -methyltransferase promotes M2 macrophage polarization by IL6 and MDSC conversion by GM-CSF in gallbladder carcinoma.

Nicotinamide N -methyltransferase (NNMT), an enzyme responsible for the methylation of nicotinamide, is involved in many metabolic pathways in adipose tissue and the liver. However, the role of NNMT in editing the tumor immune microenvironment is not well understood. Here, we identified that NNMT can promote IL6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression by decreasing the tri-methyl-histone H3 levels on the promoters of IL6 and CSF2 (encoding GM-CSF) and CCAAT/Enhancer Binding Protein, an essential transcription factor for IL6 expression, thus promoting differentiation of macrophages into M2 type tumor-associated macrophages and generation of myeloid-derived suppressor cells from peripheral blood mononuclear cells. Treatment of xenografted tumor models overexpressing NNMT gallbladder carcinoma (GBC) cells with the NNMT inhibitor JBSNF-000088 resulted in compromised tumor development and decreased expression levels of IL6, GM-CSF, tumor-associated macrophage marker CD206, and myeloid-derived suppressor cell marker CD33 but increased expression levels of CD8. In addition, elevated expression of NNMT in tumors of patients with GBC was correlated with increased expression levels of CD206 and CD33 but with decreased levels of CD8 and survival of patients. These data highlight the critical role of NNMT in GBC progression. Inhibition of NNMT by JBSNF-000088 is a potential molecular target for GBC immunotherapy.

The Therapeutic Effect of Tacrolimus in a Mouse Psoriatic Model is Associated with the Induction of Myeloid-derived Suppressor Cells.

Topical administration of Tacrolimus (TAC) is efective in the treatment of psoriasis in human patients and in mouse models. Previously, we showed that, though promoting the proliferative expansion of CD4+Foxp3+ regulatory T cells (Tregs), TNFR2 was protective in mouse psoriasis model. We thus examined the role of TNFR2 signal in the efect of TAC in the treatment of mouse psoriasis. To this end, psoriasis was induced in WT, or TNFR1 KO, or TNFR2 KO mice, and the psoriatic mice were treated with or without IMQ. The results showed that TAC treatment potently inhibited the development of psoriasis in WT and TNFR1 KO mice, but not in TNFR2 KO mice. However, the treatment of TAC failed to induce the expansion of Tregs in psoriatic mice. In addition to playing a decisive role in the activation of Tregs, TNFR2 stimulates the generation and activation of myeloid-derived suppressor cells (MDSCs). This led us to found that the topical treatment with TAC markedly increased the number of MDSCs in the spleen of WT and TNFR1 KO mice, but not in TNFR2 KO mice. Consequently, TAC potently decreased serum levels of IL-17A, INF-γ, and TNF and their mRNA levels in the inflamed skin lesion. Therefore, our study for the first time found that the therapeutic efect of TAC in psoriasis is associated with the expansion of MDSCs in a TNFR2-dependent manner.

HSP90α induces immunosuppressive myeloid cells in melanoma via TLR4 signaling

BackgroundTumor cells modulate host immunity by secreting extracellular vesicles (EV) and soluble factors. Their interactions with myeloid cells lead to the generation of myeloid-derived suppressor cells (MDSC), which inhibit the...

Sulphate repression of ssuD-dependent alkanesulphonate-sulphur assimilation in Escherichia coli.

Escherichia coli cells utilize alkanesulphonates including taurine as the sulphur source. We previously reported that when E. coli cells carrying a double deletion in tauD and cysN were inoculated into a taurine-containing minimal medium, they started to grow only after long-term incubation (Nishikawa et al. 2018, Microbiology 164: 1446-1456). We show here that cells that can induce ssuD-dependent alkanesulphonate-sulphur assimilation (SASSA) are essentially rare, but suppressors that can induce SASSA appear during long-term incubation. Mutant cells carrying ΔtauD and ΔcysN, ΔcysC or ΔcysH generated suppressor cells that can induce SASSA at a frequency of about 10-6 in a population. Whereas ΔtauD ΔcysN cells without prior SASSA did not express ssuD even when necessary, the cells with prior SASSA properly expressed ssuD. Whole-genome DNA sequencing of a clone isolated from ΔtauD ΔcysN cells with prior SASSA revealed that the influx of sulphate or thiosulphate may be related to the regulation of SASSA. To clarify whether sulphate or thiosulphate affects the induction of SASSA, the effect of mutations in sbp and cysP, which are responsible for sulphate and thiosulphate uptake with different preferences for substrates, was examined. Only the ΔtauD ΔcysN Δsbp mutant did not show repression of SASSA when no sulphate was added to the medium. When the concentration of the sulphate added was over 10 μM, the Δsbp mutant showed repression of SASSA. Therefore, it was considered that the influx of extracellular sulphate resulted in repression of SASSA.

Mesenchymal Stem Cell: A Friend or Foe in Anti-Tumor Immunity.

Mesenchymal stem cells (MSCs) are self-renewable, multipotent stem cells that regulate the phenotype and function of all immune cells that participate in anti-tumor immunity. MSCs modulate the antigen-presenting properties of dendritic cells, affect chemokine and cytokine production in macrophages and CD4+ T helper cells, alter the cytotoxicity of CD8+ T lymphocytes and natural killer cells and regulate the generation and expansion of myeloid-derived suppressor cells and T regulatory cells. As plastic cells, MSCs adopt their phenotype and function according to the cytokine profile of neighboring tumor-infiltrated immune cells. Depending on the tumor microenvironment to which they are exposed, MSCs may obtain pro- and anti-tumorigenic phenotypes and may enhance or suppress tumor growth. Due to their tumor-homing properties, MSCs and their exosomes may be used as vehicles for delivering anti-tumorigenic agents in tumor cells, attenuating their viability and invasive characteristics. Since many factors affect the phenotype and function of MSCs in the tumor microenvironment, a better understanding of signaling pathways that regulate the cross-talk between MSCs, immune cells and tumor cells will pave the way for the clinical use of MSCs in cancer immunotherapy. In this review article, we summarize current knowledge on the molecular and cellular mechanisms that are responsible for the MSC-dependent modulation of the anti-tumor immune response and we discuss different insights regarding therapeutic potential of MSCs in the therapy of malignant diseases.

Dysregulated Immunometabolism Is Associated with the Generation of Myeloid-Derived Suppressor Cells in Staphylococcus aureus Chronic Infection

Myeloid-derived suppressor cells (MDSCs) are a compendium of immature myeloid cells that exhibit potent T-cell suppressive capacity and expand during pathological conditions such as cancer and chronic infections. Although well-characterized in cancer, the physiology of MDSCs in the infection setting remains enigmatic. Here, we integrated single-cell RNA sequencing (scRNA-seq) and functional metabolic profiling to gain deeper insights into the factors governing the generation and maintenance of MDSCs in chronic Staphylococcus aureus infection. We found that MDSCs originate not only in the bone marrow but also at extramedullary sites in S. aureus-infected mice. scRNA-seq showed that infection-driven MDSCs encompass a spectrum of myeloid precursors in different stages of differentiation, ranging from promyelocytes to mature neutrophils. Furthermore, the scRNA-seq analysis has also uncovered valuable phenotypic markers to distinguish mature myeloid cells from immature MDSCs. Metabolic profiling indicates that MDSCs exhibit high glycolytic activity and high glucose consumption rates, which are required for undergoing terminal maturation. However, rapid glucose consumption by MDSCs added to infection-induced perturbations in the glucose supplies in infected mice hinders the terminal maturation of MDSCs and promotes their accumulation in an immature stage. In a proof-of-concept in vivo experiment, we demonstrate the beneficial effect of increasing glucose availability in promoting MDSC terminal differentiation in infected mice. Our results provide valuable information of how metabolic alterations induced by infection influence reprogramming and differentiation of MDSCs.

Cancer-associated fibroblasts induce monocytic myeloid-derived suppressor cell generation via IL-6/exosomal miR-21-activated STAT3 signaling to promote cisplatin resistance in esophageal squamous cell carcinoma.

Drug resistance remains the major obstacle limiting the effectiveness of chemotherapy for esophageal squamous cell carcinoma (ESCC)[1]. However, how stromal cells cooperate with immune cells to contribute to drug resistance is not yet fully understood. In this study, we observed that monocytic myeloid-derived suppressor cells (M-MDSCs) were correlated with cisplatin resistance in patients with ESCC. Furthermore, CAFs promoted differentiation of monocytes into M-MDSCs phenotypically and functionally in vitro. Mechanically, both interleukin (IL)-6 and exosome-packed microRNA-21 (miR-21) secreted by CAFs synergistically promoted the generation of M-MDSCs via activating the signal transducing activator of transcription 3 (STAT3) by IL-6 in an autocrine manner. Combined blocking of IL-6 receptor and inhibition of miR-21 significantly reversed CAF-mediated M-MDSC generation. Notably, the effects of CAFs on M-MDSC induction were abolished by inhibiting STAT3 signaling. Functionally, CAF-induced M-MDSCs promoted drug resistance of tumor cells upon cisplatin treatment. Clinically, ESCC patients with high infiltration of CAFs and CD11b+ myeloid cells had unfavorable predicted overall survival both in our cohort and in TCGA data. Taken together, our study reveals a paracrine and autocrine of IL-6 caused by CAFs co-activate STAT3 signaling, promoting the generation of M-MDSCs, and highlights the important role of CAFs in cooperation with M-MDSCs in promoting drug resistance, thus providing potential opportunities for reversing drug resistance through inhibition of STAT3 signaling.

Lysosomal Acid Lipase Is a Potential Therapeutic Target for Controlling Gvhd after Allogeneic Hematopoietic Cell Transplantation in Mice

Graft-versus-host disease (GVHD) is a main barrier for the success of allogenic hematopoietic cell transplantation (allo-HCT). Lysosomal acid lipase (LAL) mediated cell-intrinsic lipolysis to generate free fatty acids and cholesterol in the cells. It plays an essential role in the development, proliferation and function of T cells. LAL deficiency decreases Th1 and Th2 differentiation while inducing the generation of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Tregs). Treg and MDSC are suppressive and Th1/Th2/memory CD8 cells are pathogenic in GVHD. LAL is also required for CD8 memory T cells development. Due to its importance in alloreactive T cell metabolism, we hypothesize that LAL is a valid potential target for the control of GVHD.Using murine models of allo-HCT, we show here that transfer of reconstituted donor LAL-/- T-cells is associated with significantly less GVHD, compared with LAL+/+ donors in MHC-mismatched (B6->BALB/c or FVB->B6) (Figure 1A) and haploidentical (B6->BDF1) model (Figure 1B). To investigate the effect of pharmacologic LAL inhibition, Orlistat, a specific LAL inhibitor was chosen. Oral treatment of transplanted recipients with Orlistat significantly reduced GVHD severity and improves mortality of recipient mice in B6-BDF1 model. Mechanistically, LAL-/- donor T cells significantly reduced proliferation in allogeneic recipients compared to WT counterpart. Furthermore, LAL deficiency in donor T cells also reduced T cell activation and Th1 differentiation after transplantation. Strikingly, we observed that LAL-/- T-cells or Orlistat treatment largely preserved graft-versus-leukemia (GVL) activity against P815 mastocytoma in B6->BDF1 model (Figure 1, C&D).Taken all together, our current study provides evidences that LAL can be a valid target for the treatment of GVHD while maintaining GVL effect. Lipid lipase inhibitors could be a potential pharmacological agents for treating GVHD. Our findings thus explore a novel therapeutic strategy for the control of GVHD by altering lipid metabolism in donor T cells.*Hung Nguyen and Sandeepkumar Kuril contributed equally to this work [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The receptor for advanced glycation endproducts (RAGE) decreases survival of tumor-bearing mice by enhancing the generation of lung metastasis-associated myeloid-derived suppressor cells

Metastatic cancer has a poor prognosis. Novel pharmacologic targets need to be identified. The receptor for advanced glycation endproducts (RAGE) is a pattern recognition receptor constitutively expressed in the lungs. Absence of overt disease in RAGE null mice suggests that RAGE is unnecessary or redundant in health. We report that RAGE null tumor-bearing mice have reduced lung metastasis and improved survival. Bone marrow chimera studies suggest that hematopoietic cell RAGE is an important contributor to these effects. Deletion of RAGE reduces both the quantity and suppressive activity of tumor-induced MDSC. Protein and mRNA studies suggest that RAGE contributes to the generation and function of MDSC including expression of the alarmins S100A8/A9 and activity of inducible nitric oxide synthase, arginase-1, and NF-κB. These findings demonstrate the important role of RAGE in determining the quantity and function of tumor-associated MDSC and suggest RAGE as a pharmacologic target for patients with metastatic disease.

Icaritin Induces Anti-tumor Immune Responses in Hepatocellular Carcinoma by Inhibiting Splenic Myeloid-Derived Suppressor Cell Generation

Recent studies have demonstrated that splenic extramedullary hematopoiesis (EMH) is an important mechanism for the accumulation of myeloid-derived suppressor cells (MDSCs) in tumor tissues, and thus contributes to disease progression. Icaritin, a prenylflavonoid derivative from plants of the Epimedium genus, has been implicated as a novel immune-modulator that could prolong the survival of hepatocellular carcinoma (HCC) patients. However, it is unclear whether icaritin achieves its anti-tumor effects via the regulation of MDSCs generated by EMH in HCC. Here, we investigated the anti-tumor potential of icaritin and its mechanism of action in murine HCC. Icaritin suppressed tumor progression and significantly prolonged the survival of mice-bearing orthotopic and subcutaneous HCC tumors. Rather than exerting direct cytotoxic activity against tumor cells, icaritin significantly reduced the accumulation and activation of tumoral and splenic MDSCs, and increased the number and activity of cytotoxic T cells. Mechanistically, icaritin downregulates the tumor-associated splenic EMH, thereby reducing the generation and activation of MDSCs. The inhibitory effects of icaritin on human MDSCs in vitro were verified in short-term culture with cord-blood derived hematopoietic precursors. Furthermore, icaritin synergistically enhanced the therapeutic efficacy of immune checkpoint blockade therapy in HCC mice. These findings revealed that icaritin dampens tumoral immunosuppression to elicit anti-tumor immune responses by preventing MDSC generation via the attenuation of EMH. Thus, icaritin may serve as a novel adjuvant or even a stand-alone therapeutic agent for the effective treatment of HCC.

Myeloid-derived suppressor cells: Bridging the gap between inflammation and pancreatic adenocarcinoma.

Pancreatic cancer has been identified as one of the deadliest malignancies because it remains asymptomatic and usually presents in the advanced stage. Tumour immune evasion is a well-known mechanism of tumorigenesis in various forms of human malignancies. Chronic inflammation via complex networking of various inflammatory cytokines in the local tissue microenvironment dysregulates the immune system and support tumour development. Pro-inflammatory mediators present in the tumour microenvironment increase the tumour burden by causing immune suppression through the generation of myeloid-derived suppressor cells (MDSCs) and T regulatory cells. These cells, along-with myofibroblasts, create a highly immunosuppressive and resistant tumour microenvironment and are thus considered as one of the culprits for the failure of anti-cancer chemotherapies in pancreatic adenocarcinoma patients. Targeting these MDSCs using various combinatorial approaches might have the potential for abrogating the resistance and suppressive nature of the pancreatic tumour microenvironment. Therefore, there is more curiosity in studying the crosstalk of MDSCs with other immune cells during pathological conditions and the underlying mechanisms of immunosuppression in the current scenario. In this article, the possible role of MDSCs in inflammation-mediated tumour progression of pancreatic adenocarcinoma has been discussed.

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.