The Immunomodulatory Effects of Honey and Associated Flavonoids in Cancer.

Honey has exerted a high impact in the field of alternative medicine over many centuries. In addition to its wound healing, anti-microbial and antioxidant properties, several lines of evidence have highlighted the efficiency of honey and associated bioactive constituents as anti-tumor agents against a range of cancer types. Mechanistically, honey was shown to inhibit cancer cell growth through its pro-apoptotic, anti-proliferative and anti-metastatic effects. However, the potential of honey to regulate anti-tumor immune responses is relatively unexplored. A small number of in vitro and in vivo studies have demonstrated the ability of honey to modulate the immune system by inducing immunostimulatory as well as anti-inflammatory effects. In the present review, we summarize the findings from different studies that aimed to investigate the immunomodulatory properties of honey and its flavonoid components in relation to cancer. While these studies provide promising data, additional research is needed to further elucidate the immunomodulatory properties of honey, and to enable its utilization as an adjuvant therapy in cancer.

Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation.

Colchicine has served as a traditional medicine for millennia and remains widely used to treat inflammatory and other disorders. Colchicine binds tubulin and depolymerizes microtubules, but it remains unclear how this mechanism blocks myeloid cell recruitment to inflamed tissues. Here we show that colchicine inhibits myeloid cell activation via an indirect mechanism involving the release of hepatokines. We find that a safe dose of colchicine depolymerizes microtubules selectively in hepatocytes but not in circulating myeloid cells. Mechanistically, colchicine triggers Nrf2 activation in hepatocytes, leading to secretion of anti-inflammatory hepatokines, including growth differentiation factor 15 (GDF15). Nrf2 and GDF15 are required for the anti-inflammatory action of colchicine in vivo. Plasma from colchicine-treated mice inhibits inflammatory signalling in myeloid cells in a GDF15-dependent manner, by positive regulation of SHP-1 (PTPN6) phosphatase, although the precise molecular identities of colchicine-induced GDF15 and its receptor require further characterization. Our work shows that the efficacy and safety of colchicine depend on its selective action on hepatocytes, and reveals a new axis of liver-myeloid cell communication. Plasma GDF15 levels and myeloid cell SHP-1 activity may be useful pharmacodynamic biomarkers of colchicine action.

Antiproliferative Effects of St. John's Wort, Its Derivatives, and Other Hypericum Species in Hematologic Malignancies.

Hypericum is a widely present plant, and extracts of its leaves, flowers, and aerial elements have been employed for many years as therapeutic cures for depression, skin wounds, and respiratory and inflammatory disorders. Hypericum also displays an ample variety of other biological actions, such as hypotensive, analgesic, anti-infective, anti-oxidant, and spasmolytic abilities. However, recent investigations highlighted that this species could be advantageous for the cure of other pathological situations, such as trigeminal neuralgia, as well as in the treatment of cancer. This review focuses on the in vitro and in vivo antitumor effects of St. John's Wort (Hypericum perforatum), its derivatives, and other Hypericum species in hematologic malignancies. Hypericum induces apoptosis in both myeloid and lymphoid cells. Other Hypericum targets include matrix metalloproteinase-2, vascular endothelial growth factor, and matrix metalloproteinase-9, which are mediators of cell migration and angiogenesis. Hypericum also downregulates the expression of proteins that are involved in the resistance of leukemia cells to chemotherapeutic agents. Finally, Hypericum and its derivatives appear to have photodynamic effects and are candidates for applications in tumor photodynamic therapy. Although the in vitro studies appear promising, controlled in vivo studies are necessary before we can hypothesize the introduction of Hypericum and its derivatives into clinical practice for the treatment of hematologic malignancies.

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.

Sanguisorba officinalis L. derived from herbal medicine prevents intestinal inflammation by inducing autophagy in macrophages.

Disturbed activation of autophagy is implicated in the pathogenesis of inflammatory bowel disease. Accordingly, several autophagy-related genes have been identified as Crohn's disease susceptibility genes. We screened the autophagy activators from a library including 3,922 natural extracts using a high-throughput assay system. The extracts identified as autophagy activators were administered to mice with 2% dextran sodium sulfate (DSS). Among the autophagy inducers, Sanguisorba officinalis L. (SO) suppressed DSS-induced colitis. To identify the mechanism by which SO ameliorates colitis, epithelial cell and innate myeloid cells-specific Atg7-deficient mice (Villin-cre; Atg7f/f and LysM-cre; Atg7f/f mice, respectively) were analyzed. SO-mediated inhibition of colitis was observed in Villin-cre; Atg7f/f mice. However, SO and a mixture of its components including catechin acid, ellagic acid, gallic acid, and ziyuglycoside II (Mix4) did not suppressed colitis in LysM-cre; Atg7f/f mice. In large intestinal macrophages (Mφ) of Atg7f/f mice, SO and Mix4 upregulated the expression of marker genes of anti-inflammatory Mφ including Arg1, Cd206, and Relma. However, these alterations were not induced in LysM-cre; Atg7f/f mice. These findings indicate that SO and its active components ameliorate DSS-induced colitis by providing intestinal Mφ with anti-inflammatory profiles via promotion of Atg7-dependent autophagy.

Chlorella sorokiniana Extract Prevents Cisplatin-Induced Myelotoxicity In Vitro and In Vivo.

Cisplatin chemotherapy causes myelosuppression and often limits treatment duration and dose escalation in patients. Novel approaches to circumvent or lessen myelotoxicity may improve clinical outcome and quality of life in these patients. Chlorella sorokiniana (CS) is a freshwater unicellular green alga and exhibits encouraging efficacy in immunomodulation and anticancer in preclinical studies. However, the efficacy of CS on chemoprotection remains unclear. We report here, for the first time, that CS extract (CSE) could protect normal myeloid cells and PBMCs from cisplatin toxicity. Also, cisplatin-induced apoptosis in HL-60 cells was rescued through reservation of mitochondrial function, inhibition of cytochrome c release to cytosol, and suppression of caspase and PARP activation. Intriguingly, cotreatment of CSE attenuated cisplatin-evoked hypocellularity of bone marrow in mice. Furthermore, we observed the enhancement of CSF-GM activity in bone marrow and spleen in mice administered CSE and cisplatin, along with increased CD11b levels in spleen. In conclusion, we uncovered a novel mechanism of CSE on myeloprotection, whereby potentially supports the use of CSE as a chemoprotector against cisplatin-induced bone marrow toxicity. Further clinical investigation of CSE in combination with cisplatin is warranted.

Myeloid Cell-Targeted Nanocarriers Efficiently Inhibit Cellular Inhibitor of Apoptosis for Cancer Immunotherapy.

Immune-checkpoint blockers can promote sustained clinical responses in a subset of cancer patients. Recent research has shown that a subpopulation of tumor-infiltrating dendritic cells functions as gatekeepers, sensitizing tumors to anti-PD-1 treatment via production of interleukin-12 (IL-12). Hypothesizing that myeloid cell-targeted nanomaterials could be used to deliver small-molecule IL-12 inducers, we performed high-content image-based screening to identify the most efficacious small-molecule compounds. Using one lead candidate, LCL161, we created a myeloid-targeted nanoformulation that induced IL-12 production in intratumoral myeloid cells in vivo, slowed tumor growth as a monotherapy, and had no significant systemic toxicity. These results pave the way for developing combination immunotherapeutics by harnessing IL-12 production for immunostimulation.

Functional Regulation of Ginsenosides on Myeloid Immunosuppressive Cells in the Tumor Microenvironment.

Ginsenosides, the key components isolated from ginseng, have been extensively studied in antitumor treatment. Numerous studies have shown that ginsenosides have direct function in tumor cells through the induction of cancer cell apoptosis and the inhibition of cancer cell growth and enhance the antitumor immunity through the activation of cytotoxic T lymphocytes and natural killer cells. However, little is known about the function of ginsenosides on myeloid immunosuppressive cells including dendritic cells in tumor, tumor-associated macrophages, and myeloid-derived suppressor cells in the tumor microenvironments. Those myeloid immunosuppressive cells play important roles in promoting tumor angiogenesis, invasion, and metastasis. In the review, we summarize the regulatory functions of ginsenosides on myeloid immunosuppressive cells in tumor microenvironment, providing the novel therapeutic methods for clinical cancer treatment.

Fetal liver Mll-AF4+ hematopoietic stem and progenitor cells respond directly to poly(I:C), but not to a single maternal immune activation.

T(4;11) MLL-AF4 acute leukemia is one of the most aggressive malignancies in infant and pediatric populations. Epidemiological and functional studies have highlighted the influence of an overstimulation of the immune system on leukemia development. This study aimed at assessing if the cell-of-origin of t(4;11) MLL-AF4 acute leukemia is sensitive to a viral or bacterial mimic and if maternal immune activation can lead to a full-blown leukemia. To answer this, we used the Mll-AF4 pre-leukemia mouse model that initiates the expression of Mll-AF4 in the first definitive hematopoietic cells formed during embryonic development. We observed an increase in proliferation upon hematopoietic differentiation of fetal liver Mll-AF4+ Lineage-Sca1+ckit+ (LSK) cells exposed to the immune stimulants, poly(I:C) or LPS/lipopolysaccharide. This was accompanied by increased expression of a subset of MLL-AF4 signature genes and members of the Toll-like receptor signaling pathways in fetal liver Mll-AF4+ LSK exposed to poly(I:C), suggesting that the cell-of-origin responds to inflammatory stimuli. Maternal immune activation using a single dose of poly(I:C) did not lead to the development of leukemia in Mll-AF4+ and control offspring. Instead, aging MLL-AF4+ mice showed an increased proportion of T-lymphoid cells in the spleen, lost their B-lymphoid bias, and had decreased frequencies of hematopoietic stem and multipotent progenitor cells. Overall, this study suggests that the fetal liver Mll-AF4+ LSK cells are sensitive to direct exposure to inflammatory stimuli, especially poly(I:C); however, maternal immune activation induced by a single exposure to poly(I:C) is not sufficient to initiate MLL-AF4 leukemogenesis.

Gexia-Zhuyu Decoction Attenuates Carbon Tetrachloride-Induced Liver Fibrosis in Mice Partly via Liver Angiogenesis Mediated by Myeloid Cells.

BACKGROUND This study aims to demonstrate the underlying correlation between the resolution of liver fibrosis induced by Gexia-Zhuyu decoction (GZD) treatment and myeloid cell-mediated angiogenesis. MATERIAL AND METHODS A liver fibrosis mouse model induced by carbon tetrachloride (CCl4) intervention was employed in this study. Dynamics of blood liver function parameters were followed. The liver pathology was detected by Sirius Red and Masson staining. Matrix metalloproteinase (MMP) 2/9, tissue inhibitors of metalloproteinase (TIMP)-1/2, and vascular endothelial growth factor (VEGF)-A expression levels were measured. Bone marrow chimera mice were generated by transfer of bone morrow cells from green fluorescent protein (GFP)-knockin mice into irradiated wild-type mice, and were used it to visualize the role of myeloid cells on the fibrosis resolution induced by GZD treatment. RESULTS The result of Sirius Red and Masson staining and the dynamics of blood liver function parameters showed that 5 weeks of GZD treatment attenuated the severity of liver fibrosis with continual CCl4 administration. GZD treatment promoted the expression of MMP2/9 and repressed the heightened level of TIMP-1/2 in the recovery phase. More notably, the increased VEGF-A and augmented endothelial progenitor cells were observed in the liver and blood in mice that received GZD, and contributed to the remodeling of hepatic vascular though the CXCL12/CXCR4 axis. Then, chimera mice with GFP-positive bone marrow cells were used to show angiogenesis driven by GZD-induced myeloid cell motivation. We found that GZD facilitated myeloid cells binding to the vascular CXCR4 and induced the resolution of fibrosis. CONCLUSIONS This study shows that activation of myeloid cells induced by GZD administration accelerates the functional angiogenesis, which benefits the resolution of CCl4-induced liver fibrosis.

Btk inhibitor ibrutinib reduces inflammatory myeloid cell responses in the lung during murine pneumococcal pneumonia.

BACKGROUND: Streptococcus pneumoniae is a major causative agent in community-acquired pneumonia and sepsis. Overwhelming lung inflammation during pneumococcal pneumonia may hamper lung function. Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (Btk), a key signaling protein controlling the activation of various immune cells, including macrophages and neutrophils. The aim of this study was to determine whether ibrutinib treatment ameliorates acute lung inflammation during pneumococcal pneumonia. METHODS: Mice were treated orally with ibrutinib and the effect on acute pulmonary inflammation elicited by the gram-positive bacterial cell wall component lipoteichoic acid (LTA) and during ceftriaxone-treated pneumococcal pneumonia was assessed. RESULTS: Treatment with ibrutinib prior to and after intranasal LTA instillation reduced alveolar macrophage activation, neutrophil influx, cytokine release and plasma leakage into the lung. Postponed treatment with ibrutinib supplementing antibiotic therapy during ongoing pneumococcal pneumonia did not impair bacterial killing in lung, blood and spleen. In this setting, ibrutinib reduced alveolar macrophage and systemic neutrophil activation and substantially diminished further monocyte and neutrophil influx in the lung. In vitro, ibrutinib inhibited macrophage TNF secretion and neutrophil activation upon LTA and pneumococcal stimulation. CONCLUSIONS: Taken together, these data indicate that the Btk inhibitor ibrutinib reduces inflammatory myeloid cell responses during acute pulmonary inflammation evoked by LTA and antibiotic-treated pneumococcal pneumonia and suggest that ibrutinib has the potential to inhibit ongoing lung inflammation in an acute infectious setting.

Study of the Effects and Mechanisms of Ginsenoside Compound K on Myelosuppression.

Ginsenoside compound K (CK) is not a ginsenoside that naturally exists in Panax ginseng Meyer. However, CK is a major metabolite of ginsenoside Rb1, Rb2, or Rc in the intestine under the effects of bacteria. In this study, we first investigated the effects of CK on myelosuppression in mice induced by cyclophosphamide (CTX). The respective quantities of white blood cells, blood platelets, and bone marrow nucleated cells (BMNCs) were determined to be 8.54 ± 0.91 (109/L), 850.90 ± 44.11 (109/L), and 1.45 ± 0.22 (109/L) in the CK-H group by detecting peripheral blood cells and BMNCs. CK-H and CK-L both increased the thymus index by up to 0.62 ± 0.06 (mg/g) and 0.52 ± 0.09 (mg/g), respectively, and significantly increased the yields of colony formation units-granulocyte monocyte and colony formation units-megakaryocytic. According to our study, CK could control apoptosis and promote cells to enter the normal cell cycle by the bcl-2/bax signaling pathway and MEK/ERK signaling pathway. Therefore, the BMNCs could proliferate and differentiate normally after entering the normal cell cycle. So the peripheral blood cells could show a trend of returning to normal. The recovery of peripheral blood cells resulting in the level of cytokines tended to normal. This process may be the mechanisms of CK on myelosuppression. This study provides a reference for ginseng in the treatment of myelosuppression.

miR-130a and miR-145 reprogram Gr-1+CD11b+ myeloid cells and inhibit tumor metastasis through improved host immunity.

Tumor-derived soluble factors promote the production of Gr-1+CD11b+ immature myeloid cells, and TGFß signaling is critical in their immune suppressive function. Here, we report that miR-130a and miR-145 directly target TGFß receptor II (TßRII) and are down-regulated in these myeloid cells, leading to increased TßRII. Ectopic expression of miR-130a and miR-145 in the myeloid cells decreased tumor metastasis. This is mediated through a downregulation of type 2 cytokines in myeloid cells and an increase in IFNγ-producing cytotoxic CD8 T lymphocytes. miR-130a- and miR-145-targeted molecular networks including TGFß and IGF1R pathways were correlated with higher tumor stages in cancer patients. Lastly, miR-130a and miR-145 mimics, as well as IGF1R inhibitor NT157 improved anti-tumor immunity and inhibited metastasis in preclinical mouse models. These results demonstrated that miR-130a and miR-145 can reprogram tumor-associated myeloid cells by altering the cytokine milieu and metastatic microenvironment, thus enhancing host antitumor immunity.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid or myeloid cells surface antigens [II]: CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4).

BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of agents targeting CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4 and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: The risk and spectrum of infections in patients receiving CD22-targeted agents (i.e. inotuzumab ozogamicin) are similar to those observed with anti-CD20 antibodies. Anti-Pneumocystis prophylaxis and monitoring for cytomegalovirus (CMV) infection is recommended for patients receiving CD30-targeted agents (brentuximab vedotin). Due to the scarcity of data, the risk posed by CD33-targeted agents (gemtuzumab ozogamicin) cannot be assessed. Patients receiving CD38-targeted agents (i.e. daratumumab) face an increased risk of varicella-zoster virus (VZV) infection. Therapy with CD40-targeted agents (lucatumumab or dacetuzumab) is associated with opportunistic infections similar to those observed in hyper-IgM syndrome, and prevention strategies (including anti-Pneumocystis prophylaxis and pre-emptive therapy for CMV infection) are warranted. SLAMF-7 (CD319)-targeted agents (elotuzumab) induce lymphopenia and increase the risk of infection (particularly due to VZV). The impact of CCR4-targeted agents (mogamulizumab) on infection susceptibility is difficult to distinguish from the effect of underlying diseases and concomitant therapies. However, anti-Pneumocystis and anti-herpesvirus prophylaxis and screening for chronic hepatitis B virus (HBV) infection are recommended. IMPLICATIONS: Specific management strategies should be put in place to reduce the risk and/or the severity of infectious complications associated to the reviewed agents.

Activation of 4-1BB on Liver Myeloid Cells Triggers Hepatitis via an Interleukin-27-Dependent Pathway.

Purpose: Agonist antibodies targeting the T-cell costimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across preclinical cancer models. In the clinic, however, development of these agents has been hampered by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist-driven tumor immunity from hepatotoxicity.Experimental Design: The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in immunocompetent mice, with or without coadministration of checkpoint blockade, via (i) measurement of serum transaminase levels, (ii) imaging of liver immune infiltrates, and (iii) qualitative and quantitative assessment of liver myeloid and T cells via flow cytometry. Knockout mice were used to clarify the contribution of specific cell subsets, cytokines, and chemokines.Results: We find that activation of 4-1BB on liver myeloid cells is essential to initiate hepatitis. Once activated, these cells produce interleukin-27 that is required for liver toxicity. CD8 T cells infiltrate the liver in response to this myeloid activation and mediate tissue damage, triggering transaminase elevation. FoxP3+ regulatory T cells limit liver damage, and their removal dramatically exacerbates 4-1BB agonist-induced hepatitis. Coadministration of CTLA-4 blockade ameliorates transaminase elevation, whereas PD-1 blockade exacerbates it. Loss of the chemokine receptor CCR2 blocks 4-1BB agonist hepatitis without diminishing tumor-specific immunity against B16 melanoma.Conclusions: 4-1BB agonist antibodies trigger hepatitis via activation and expansion of interleukin-27-producing liver Kupffer cells and monocytes. Coadministration of CTLA-4 and/or CCR2 blockade may minimize hepatitis, but yield equal or greater antitumor immunity. Clin Cancer Res; 24(5); 1138-51. ©2018 AACR.

Ginseng-Derived Panaxadiol Saponins Promote Hematopoiesis Recovery in Cyclophosphamide-Induced Myelosuppressive Mice: Potential Novel Treatment of Chemotherapy-Induced Cytopenias.

OBJECTIVE: To investigate the potential efficacy of panaxadiol saponins component (PDS-C), a biologically active fraction isolated from total ginsenosides, to reverse chemotherapy-induced myelosuppression and pancytopenia caused by cyclophamide (CTX). METHODS: Mice with myelosuppression induced by CTX were treated with PDS-C at a low- (20 mg/kg), moderate- (40 mg/kg), or high-dose (80 mg/kg) for 7 consecutive days. The level of peripheral white blood cell (WBC), neutrophil (NEU) and platelet (PLT) were measured, the histopathology and colony formation were observed, the protein kinase and transcription factors in hematopoietic cells were determined by immunohistochemical staining and Western blot. RESULTS: In response to PDS-C therapy, the peripheral WBC, NEU and PLT counts of CTX-induced myelosuppressed mice were significantly increased in a dose-dependent manner. Similarly, bone marrow histopathology examination showed reversal of CTX-induced myelosuppression with increase in overall bone marrow cellularity and the number of hematopoietic cells (P<0.01). PDS-C also promoted proliferation of granulocytic and megakaryocyte progenitor cells in CTX-treated mice, as evidenced by significantly increase in colony formation units-granulocytes/monocytes and -megakaryocytes (P<0.01). The enhancement of hematopoiesis by PDS-C appears to be mediated by an intracellular signaling pathway, this was evidenced by the up-regulation of phosphorylated mitogen-activated protein kinase (p-MEK) and extracellular signal-regulated kinases (p-ERK), and receptor tyrosine kinase (C-kit) and globin transcription factor 1 (GATA-1) in hematopoietic cells of CTX-treated mice (P<0.05). CONCLUSIONS: PDS-C possesses hematopoietic growth factor-like activities that promote proliferation and also possibly differentiation of hematopoietic progenitor cells in myelosuppressed mice, probably mediated by a mechanism involving MEK and ERK protein kinases, and C-kit and GATA-1 transcription factors. PDS-C may potentially be a novel treatment of myelosuppression and pancytopenia caused by chemotherapy.

Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are frequently found in several human cancer types including acute myeloid leukemia (AML) and lead to the production of high levels of the oncometabolite (R)-2-hydroxyglutarate (R-2HG). Here we report the characterization of BAY1436032, a novel pan-mutant IDH1 inhibitor, both in vitro and in vivo. BAY1436032 specifically inhibits R-2HG production and colony growth, and induces myeloid differentiation of AML cells carrying IDH1R132H, IDH1R132C, IDH1R132G, IDH1R132L and IDH1R132S mutations. In addition, the compound impacts on DNA methylation and attenuates histone hypermethylation. Oral administration of BAY1436032 led to leukemic blast clearance, myeloid differentiation, depletion of leukemic stem cells and prolonged survival in two independent patient-derived xenograft IDH1 mutant AML mouse models. Together, BAY1436032 is highly effective against all major types of IDH1 mutant AML.

Erythropoietin modulation is associated with improved homing and engraftment after umbilical cord blood transplantation.

Umbilical cord blood (UCB) engraftment is in part limited by graft cell dose, generally one log less than that of bone marrow (BM)/peripheral blood (PB) cell grafts. Strategies toward increasing hematopoietic stem/progenitor cell (HSPC) homing to BM have been assessed to improve UCB engraftment. Despite recent progress, a complete understanding of how HSPC homing and engraftment are regulated is still elusive. We provide evidence that blocking erythropoietin (EPO)-EPO receptor (R) signaling promotes homing to BM and early engraftment of UCB CD34+ cells. A significant population of UCB CD34+ HSPC expresses cell surface EPOR. Exposure of UCB CD34+ HSPC to EPO inhibits their migration and enhances erythroid differentiation. This migratory inhibitory effect was reversed by depleting EPOR expression on HSPC. Moreover, systemic reduction in EPO levels by hyperbaric oxygen (HBO) used in a preclinical mouse model and in a pilot clinical trial promoted homing of transplanted UCB CD34+ HSPC to BM. Such a systemic reduction of EPO in the host enhanced myeloid differentiation and improved BM homing of UCB CD34+ cells, an effect that was overcome with exogenous EPO administration. Of clinical relevance, HBO therapy before human UCB transplantation was well-tolerated and resulted in transient reduction in EPO with encouraging engraftment rates and kinetics. Our studies indicate that systemic reduction of EPO levels in the host or blocking EPO-EPOR signaling may be an effective strategy to improve BM homing and engraftment after allogeneic UCB transplantation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT02099266).

Onionin A, a sulfur-containing compound isolated from onions, impairs tumor development and lung metastasis by inhibiting the protumoral and immunosuppressive functions of myeloid cells.

SCOPE: Recent studies have demonstrated that myeloid lineage cells, such as macrophages and myeloid suppressor cells (MDSCs), are major components exhibiting protumoral functions in the setting of tumor progression. Tumor-associated macrophages polarized to the protumoral M2 phenotype promote tumor proliferation and are considered to be a therapeutic target in patients with malignant tumors. METHODS AND RESULTS: We identified a new candidate compound, called onionin A (ONA) isolated from onions, that inhibits macrophage polarization into the M2 phenotype, as well as the immunosuppressive activity of MDSCs and tumor proliferation, by suppressing signal transducer and activator of transcription-3 (Stat3) activation. Furthermore, ONA administration was found to significantly suppress subcutaneous tumor development and lung metastasis in tumor-bearing mice. ONA administration also inhibited Stat3 activation and increased the number of infiltrating lymphocytes in tumor tissues, and an ex vivo analysis showed that the immunosuppressive effect of MDSCs in tumor-bearing mice is impaired by ONA. Moreover, ONA regulated tumor proliferation by inhibiting cell-cell interactions between macrophages and tumor cells, and ONA administration enhanced the antitumor effects of cisplatin in the tumor-bearing mice. CONCLUSIONS: These findings demonstrate that ONA may be a potential new tool for antitumor therapy and also for tumor prevention.

The anti-tumor effect of the quinoline-3-carboxamide tasquinimod: blockade of recruitment of CD11b(+) Ly6C(hi) cells to tumor tissue reduces tumor growth.

BACKGROUND: Previous work has demonstrated immunomodulatory, anti-tumor, anti-metastatic and anti-angiogenic effects of the small molecule quinoline-3-carboxamide tasquinimod in pre-clinical cancer models. To better understand the anti-tumor effects of tasquinimod in transplantable tumor models, we have evaluated the impact of the compound both on recruitment of myeloid cells to tumor tissue and on tumor-induced myeloid cell expansion as these cells are known to promote tumor development. METHODS: Mice bearing subcutaneous 4 T1 mammary carcinoma tumors were treated with tasquinimod in the drinking water. A BrdU-based flow cytometry assay was utilized to assess the impact of short-term tasquinimod treatment on myeloid cell recruitment to tumors. Additionally, long-term treatment was performed to study the anti-tumor effect of tasquinimod as well as its effects on splenic myeloid cells and their progenitors. Myeloid cell populations were also immune-depleted by in vivo antibody treatment. RESULTS: Short-term tasquinimod treatment did not influence the proliferation of splenic Ly6C(hi) and Ly6G(hi) cells, but instead reduced the influx of Ly6C(hi) cells to the tumor. Treatment with tasquinimod for various periods of time after tumor inoculation revealed that the anti-tumor effect of this compound mainly operated during the first few days of tumor growth. Similar to tasquinimod treatment, antibody-mediated depletion of Ly6C(hi) cells within that same time frame, caused reduced tumor growth, thereby confirming a significant role for these cells in tumor development. Additionally, long-term tasquinimod treatment reduced the splenomegaly and expansion of splenic myeloid cells during a later phase of tumor development. In this phase, tasquinimod normalized the tumor-induced alterations in myeloerythroid progenitor cells in the spleen but had only limited impact on the same populations in the bone marrow. CONCLUSIONS: Our results indicate that tasquinimod treatment reduces tumor growth by operating early after tumor inoculation and that this effect is at least partially caused by reduced recruitment of Ly6C(hi) cells to tumor tissue. Long-term treatment also reduces the number of splenic myeloid cells and myeloerythroid progenitors, but these effects did not influence established rapidly growing tumors.