Explore the vast range of titles available.

Myeloid-derived suppressor cells (MDSC) are pathologically activated neutrophils and monocytes with potent immune suppressive activity. These cells play an important role in accelerating tumor progression and undermining the efficacy of anti-cancer therapies. The natural mechanisms limiting MDSC activity are not well understood. Here, we present evidence that type I interferons (IFN1) receptor signaling serves as a universal mechanism that restricts acquisition of suppressive activity by these cells. Downregulation of the IFNAR1 chain of this receptor is found in MDSC from cancer patients and mouse tumor models. The decrease in IFNAR1 depends on the activation of the p38 protein kinase and is required for activation of the immune suppressive phenotype. Whereas deletion of IFNAR1 is not sufficient to convert neutrophils and monocytes to MDSC, genetic stabilization of IFNAR1 in tumor bearing mice undermines suppressive activity of MDSC and has potent antitumor effect. Stabilizing IFNAR1 using inhibitor of p38 combined with the interferon induction therapy elicits a robust anti-tumor effect. Thus, negative regulatory mechanisms of MDSC function can be exploited therapeutically. The role of type I interferon signalling in the control of myeloid derived suppressor cells (MDSC) activity remains controversial. Here the authors show that downregulation of type I interferon receptor is observed in MDSC from cancer patients and tumor-bearing mice and is required for the activation of their immune suppressive properties.

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that are crucial for the regulation of immune responses in cancer. These cells contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite recent advances in the understanding of PMN-MDSC biology, the mechanisms responsible for the pathological activation of neutrophils are not well defined, and this limits the selective targeting of these cells. Here we report that mouse and human PMN-MDSCs exclusively upregulate fatty acid transport protein 2 (FATP2). Overexpression of FATP2 in PMN-MDSCs was controlled by granulocyte–macrophage colony-stimulating factor, through the activation of the STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSCs. The main mechanism of FATP2-mediated suppressive activity involved the uptake of arachidonic acid and the synthesis of prostaglandin E 2 . The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSCs and substantially delayed tumour progression. In combination with checkpoint inhibitors, FATP2 inhibition blocked tumour progression in mice. Thus, FATP2 mediates the acquisition of immunosuppressive activity by PMN-MDSCs and represents a target to inhibit the functions of PMN-MDSCs selectively and to improve the efficiency of cancer therapy. The lipid transporter FATP2 reprograms neutrophils to polymorphonuclear myeloid-derived suppressor cells by mediating the uptake of arachidonic acid and promoting the synthesis of prostaglandin E 2 .

Myeloid-derived suppressor cells are induced in newborn mice by breast-milk-derived lactoferrin and confer protection in a model of necrotizing enterocolitis. Their frequency and suppressive activity is decreased in very low-weight infants. Myeloid-derived suppressor cells (MDSCs) are pathologically activated and relatively immature myeloid cells that have been implicated in the immunological regulation of many pathologic conditions 1 , 2 . Phenotypically and morphologically, MDSCs are similar to neutrophils (PMN-MDSCs) and monocytes (M-MDSCs). However, they have potent suppressive activity and distinct gene expression profiles and biochemical characteristics 3 . No or very few MDSCs are observed in steady-state physiological conditions. Therefore, until recently, accumulation of MDSCs was considered a consequence of pathological processes or pregnancy. Here, we report that MDSCs with a potent ability to suppress T cells are present during the first weeks of life in mice and humans. MDSC suppressive activity was triggered by lactoferrin and mediated by nitric oxide, PGE2, and S100A9 and S100A8 proteins. MDSCs from newborns had a transcriptome similar to that of tumor MDSCs, but with strong upregulation of an antimicrobial gene network, and had potent antibacterial activity. MDSCs played a critical role in control of experimental necrotizing enterocolitis (NEC) in newborn mice. MDSCs in infants with very low weight, who are prone to NEC, had lower MDSC levels and suppressive activity than did infants with normal weight. Thus, the transitory presence of MDSCs may be critical for regulation of inflammation in newborns.

Although neutrophils have been linked to the formation of the pre-metastatic niche, the mechanism of their migration to distant, uninvolved tissues has remained elusive. We report that bone marrow neutrophils from mice with early-stage cancer exhibited much more spontaneous migration than that of control neutrophils from tumor-free mice. These cells lacked immunosuppressive activity but had elevated rates of oxidative phosphorylation and glycolysis, and increased production of ATP, relative to that of control neutrophils. Their enhanced spontaneous migration was mediated by autocrine ATP signaling through purinergic receptors. In ectopic tumor models and late stages of cancer, bone marrow neutrophils demonstrated potent immunosuppressive activity. However, these cells had metabolic and migratory activity indistinguishable from that of control neutrophils. A similar pattern of migration was observed for neutrophils and polymorphonuclear myeloid-derived suppressor cells from patients with cancer. These results elucidate the dynamic changes that neutrophils undergo in cancer and demonstrate the mechanism of neutrophils’ contribution to early tumor dissemination. Neutrophils are linked to tumor progression. Gabrilovich and colleagues demonstrate that neutrophils have tumor-stage-dependent alterations in motility, function and metabolism: in early phases, they are highly motile with altered metabolism, whereas at later stages, they become highly suppressive.

Gabrilovich and colleagues show that monocytic myeloid-derived suppressor cells (MDSCs) differentiate into polymorphonuclear MDSCs in individuals with tumors, demonstrating a demonstrating a distinct regulation of myeloid cell development in cancer. Two major populations of myeloid-derived suppressor cells (MDSCs), monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) regulate immune responses in cancer and other pathologic conditions. Under physiologic conditions, Ly6C hi Ly6G − inflammatory monocytes, which are the normal counterpart of M-MDSCs, differentiate into macrophages and dendritic cells. PMN-MDSCs are the predominant group of MDSCs that accumulates in cancer. Here we show that a large proportion of M-MDSCs in tumor-bearing mice acquired phenotypic, morphological and functional features of PMN-MDSCs. Acquisition of this phenotype, but not the functional attributes of PMN-MDSCs, was mediated by transcriptional silencing of the retinoblastoma gene through epigenetic modifications mediated by histone deacetylase 2 (HDAC-2). These data demonstrate a new regulatory mechanism of myeloid cells in cancer.

The origin of breast cancer, whether primary or recurrent, is unknown. Here, we show that invasive breast cancer cells exposed to hypoxia release small extracellular vesicles (sEVs) that disrupt the differentiation of normal mammary epithelia, expand stem and luminal progenitor cells, and induce atypical ductal hyperplasia and intraepithelial neoplasia. This was accompanied by systemic immunosuppression with increased myeloid cell release of the alarmin S100A9 and oncogenic traits of epithelial-mesenchymal transition, angiogenesis, and local and disseminated luminal cell invasion in vivo. In the presence of a mammary gland driver oncogene (MMTV-PyMT), hypoxic sEVs accelerated bilateral breast cancer onset and progression. Mechanistically, genetic or pharmacologic targeting of hypoxia-inducible factor-1α (HIF1α) packaged in hypoxic sEVs or homozygous deletion of S100A9 normalized mammary gland differentiation, restored T cell function, and prevented atypical hyperplasia. The transcriptome of sEV-induced mammary gland lesions resembled luminal breast cancer, and detection of HIF1α in plasma circulating sEVs from luminal breast cancer patients correlated with disease recurrence. Therefore, sEV-HIF1α signaling drives both local and systemic mechanisms of mammary gland transformation at high risk for evolution to multifocal breast cancer. This pathway may provide a readily accessible biomarker of luminal breast cancer progression.

Canonical Wnt signaling has been implicated in the regulation of multiple myeloma (MM) growth. Here, we investigated whether the targeting of this pathway with a novel pharmacological inhibitor ICG-001 would result in an anti-tumor effect and improvement of chemosensitivity in MM. As expected, ICG-001 specifically down-regulated β-catenin/TCF-mediated transcription in MM cells. Treatment with ICG-001 resulted in growth arrest and apoptosis in MM cell lines and primary MM cells. Moreover, ICG-001 enhanced the cytotoxic effects of doxorubicin and melphalan and abrogated chemoresistance of MM cells to these chemotherapeutics induced by bone marrow stroma. The cytotoxic effect of ICG-001 was caspase-dependent and mediated through transcriptional up-regulation of BH3-only pro-apoptotic members of the Bcl-2 family Noxa and Puma but not through inhibition of canonical Wnt signaling. ICG-001 selectively induced apoptosis in primary MM cells but did not affect non-MM cells of the bone marrow microenvironment. Experiments using a xenograft model of MM showed substantial anti-tumor effects of this compound in vivo. Thus, our study demonstrated that the small molecule inhibitor ICG-001 has strong anti-MM effects and could be developed further for therapeutic intervention in this disease.

BackgroundOvarian cancer (OvCa) is the most lethal gynecological cancer and the fifth leading cause of cancer-related deaths in women. Despite an initial positive response to therapy, most patients relapse and present with chemotherapy resistance. The prognosis for recurrent disease is poor, with a 5-year survival rate of < 30%. One contributor to disease recurrence and therapy resistance is the presence of disseminated cancer cells that remain in the peritoneal fluid after treatment. A growing body of evidence suggests that these cells exhibit dormancy characteristics that render them resistant to most therapies. Moreover, cancer cells in fluid are unable to be surgically resected. Because 75% of relapsed patients present with therapy-resistant intraperitoneal disease, developing new strategies to effectively target disseminating OvCa cells in the peritoneal fluid is crucial for the effective treatment of OvCa. Two key players in peritoneal immunity, the omentum and peritoneal resident macrophages (PRMΦs), are known to sequester pathogens in the peritoneal fluid and coordinate an inflammatory immune response in the peritoneum. One such activator of peritoneal immunity is β-glucan, a sugar found on the cell walls of yeasts.ObjectiveTo target disseminating OvCa cells in the peritoneal fluid by activating myeloid cells in the peritoneal cavity via intraperitoneal administration of β-glucan.MethodsC57bl/6J mice were injected with GFP-labeled murine OvCa cells (KPCA: Trp53 −/−R172H Ccne1 OE Akt2 OE KRAS G12V) immediately followed by 500μg β-glucan (i.p.). Five hours later, mice were euthanized and their peritoneal lavage was analyzed for the presence of OvCa cells. To model advanced disease, Luciferase-KPCA cells were seeded in C57bl/6J mice one week prior to biweekly β-glucan treatment and imaged 3 weeks later.ResultsFirst, we found that β-glucan was highly efficient in acutely clearing OvCa cells from the peritoneal fluid. Mechanistically, β-glucan captured free-floating OvCa cells into solid nodules through two non-redundant and equally important pathways: (1) an unexpected Dectin-1/SYK-independent, heparin-sensitive pathway that was mediated by PRMΦ aggregation in the peritoneal fluid; and (2) a Dectin-1/SYK/PAD4-dependent pathway that was mediated by neutrophil extracellular traps in the omentum. Second, we found that β-glucan also completely cleared cancer from the peritoneal fluid and prevented ascites accumulation in advanced disease. Combining β-glucan with IFNγ (β-glucan/IFNγ) not only cleared ascites but also regressed omentum tumors and prevented intraperitoneal metastases as compared to PBS-, β-glucan-, or IFNγ-treated mice.ConclusionsIntraperitoneal injection of β-glucan clears OvCa cells from the peritoneal fluid and has therapeutic potential to control OvCa metastasis.

Neutrophils have a pivotal role in safeguarding the host against pathogens and facilitating tissue remodeling. They possess a large array of tools essential for executing these functions. Neutrophils have a critical role in cancer, where they are largely associated with negative clinical outcome and resistance to therapy. However, the specific role of neutrophils in cancer is complex and controversial, owing to their high functional diversity and acute sensitivity to the microenvironment. In this Perspective, we discuss the accumulated evidence that suggests that the functional diversity of neutrophils can be ascribed to two principal functional states, each with distinct characteristics: classically activated neutrophils and pathologically activated immunosuppressive myeloid-derived suppressor cells. We discuss how the antimicrobial factors in neutrophils can contribute to tumor progression and the fundamental mechanisms that govern the pathologically activated myeloid-derived suppressor cells. These functional states play divergent roles in cancer and thus require separate consideration in therapeutic targeting. Gabrilovich and colleagues discuss how the functional diversity of neutrophils in cancer can be ascribed to two functional states: classically activated neutrophils and pathologically activated myeloid-derived suppressor cells.

Ferroptosis is a non-apoptotic form of regulated cell death that is triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Ferroptosis inducers have shown considerable effectiveness in killing tumour cells in vitro, yet there has been no obvious success in experimental animal models, with the notable exception of immunodeficient mice 1 , 2 . This suggests that the effect of ferroptosis on immune cells remains poorly understood. Pathologically activated neutrophils (PMNs), termed myeloid-derived suppressor cells (PMN-MDSCs), are major negative regulators of anti-tumour immunity 3 – 5 . Here we found that PMN-MDSCs in the tumour microenvironment spontaneously die by ferroptosis. Although decreasing the presence of PMN-MDSCs, ferroptosis induces the release of oxygenated lipids and limits the activity of human and mouse T cells. In immunocompetent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSCs, reduces tumour progression and synergizes with immune checkpoint blockade to suppress the tumour growth. By contrast, induction of ferroptosis in immunocompetent mice promotes tumour growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSCs in the tumour microenvironment that can be pharmacologically modulated to limit tumour progression. Pathologically activated neutrophils, termed myeloid-derived suppressor cells, in the tumour microenvironment spontaneously undergo ferroptosis, which negatively regulates anti-tumour immunity through the release of oxygenated lipids, therefore limiting the activity of human and mouse T cells.