Myeloid-derived suppressor cells (MDSC) are one of the major factors limiting immune response in cancer. However, their role in bone marrow (BM), the site of primary localization of multiple myeloma (MM), is poorly understood. In this study we found a significant accumulation of CD11b+CD14−CD33+ immune suppressive MDSC in BM of patients with newly diagnosed MM. To assess the possible role of MDSC in MM, we used immune competent mouse models. Immune suppressive MDSC accumulated in BM of mice as early as one week after tumor inoculation. S100A9 knockout (KO) mice, which are deficient in their ability to accumulate MDSC in tumor-bearing hosts, demonstrated reduced MDSC accumulation in BM after injection of MM cells as compared to wild-type mice. Growth of the immunogenic MM cells was significantly reduced in S100A9KO mice. This effect was associated with the accumulation of antigen-specific CD8+ T cells in BM and spleens of S100A9KO, but not wild-type mice, and was abrogated by the administration of anti-CD8 antibody or adoptive transfer of MDSC. Thus, the accumulation of MDSC at early stages of MM plays a critical role in the MM progression and suggests that MDSC can be considered as a possible therapeutic target in this disease.

This is an unequivocal demonstration of gene transfer between two strains co-residing in the human gut, as the donor, recipient and transconjugant strains were isolated. The results suggest the dynamic adaptation by commensal bacteria in response to antibiotic treatment may occur readily.

Streptococcus pneumoniae is a major cause of otitis media, pneumonia, meningitis, and septicemia in humans. The host defense against this pathogen largely depends on bacterial killing by neutrophils. A peculiar property of pneumococci is their tendency to undergo autolysis, i.e., autoinduced disruption of the bacterial cell wall mediated by activation of the enzyme LytA, under stationary growth conditions. LytA is a virulence factor, but the molecular background for this has not been fully clarified. Here we examine how bacterial compounds released upon autolysis affect the production of reactive oxygen species (ROS) in neutrophils. We found that the S. pneumoniae strains A17 and D39 induced activation of the NADPH oxidase and the production of ROS in human neutrophils and that this activation was blocked when LytA was inactivated. The ROS-inducing bacterial substance released from autolyzed bacteria was identified as the cytoplasmic toxin pneumolysin. Further screening of clinical pneumococcal strains of various sero-and genotypes revealed that selected strains expressing toxins with reduced pneumolysin-dependent hemolytic activity had decreased abilities to induce ROS in neutrophils. Furthermore, a mutated form of purified pneumolysin lacking hemolytic and complement binding functions (PdT) did not induce any oxygen radical production. The ROS produced in response to pneumolysin formed mainly intracellularly, which may explain why this production was not detected previously. ROS released intracellularly may function as signaling molecules, modifying the function of neutrophils in bacterial defense.

The NADPH oxidase of myeloid cells, NOX2, generates reactive oxygen species (ROS) to eliminate pathogens and malignant cells. NOX2-derived ROS have also been proposed to dampen functions of natural killer (NK) cells and other antineoplastic lymphocytes in the microenvironment of established tumors. The mechanisms by which NOX2 and ROS influence the process of distant metastasis have only been partially explored. Here, we utilized genetically NOX2-deficient mice and pharmacologic inhibition of NOX2 to elucidate the role of NOX2 for the hematogenous metastasis of melanoma cells. After intravenous inoculation of B16F1 or B16F10 cells, lung metastasis formation was reduced in B6.129S6-Cybb tm1DinK (Nox2-KO) versus Nox2-sufficient wild-type (WT) mice. Systemic treatment with the NOX2-inhibitor histamine dihydrochloride (HDC) reduced melanoma metastasis and enhanced the infiltration of IFNg-producing NK cells into lungs of WT but not of Nox2-KO mice. IFNg-deficient B6.129S7-Ifng tm1Ts /J mice were prone to develop melanoma metastases and did not respond to in vivo treatment with HDC. We propose that NOX2-derived ROS facilitate metastasis of melanoma cells by downmodulating NK-cell function and that inhibition of NOX2 may restore IFNg-dependent, NK cell-mediated clearance of melanoma cells. Cancer Immunol Res; 5(9); 804-11. Ó2017AACR.

Redox regulation has been proposed to control various aspects of carcinogenesis, cancer cell growth, metabolism, migration, invasion, metastasis and cancer vascularization. As cancer has many faces, the role of redox control in different cancers and in the numerous cancer-related processes often point in different directions. In this review, we focus on the redox control mechanisms of tumor cell destruction. The review covers the tumor-intrinsic role of oxidants derived from the reduction of oxygen and nitrogen in the control of tumor cell proliferation as well as the roles of oxidants and antioxidant systems in cancer cell death caused by traditional anticancer weapons (chemotherapeutic agents, radiotherapy, photodynamic therapy). Emphasis is also put on the role of oxidants and redox status in the outcome following interactions between cancer cells, cytotoxic lymphocytes and tumor infiltrating macrophages.

Dysfunction of T cells and natural killer (NK) cells has been proposed to deter- IntroductionAcute myeloid leukemia (AML) is characterized by a deficiency of hematopoietic progenitor and stem cell development with a resulting accumulation of immature myeloid cells in BM. [1][2][3] The current treatment in AML comprises an initial phase of intensive chemotherapy, induction, and consolidation that aims to achieve and maintain complete remission (CR). 4,5 Younger patients may subsequently undergo allogeneic stem cell transplantation, 6 whereas few therapeutic options are available in the postconsolidation phase for other patients. 7 The occurrence of relapse after CR along with the poor postrelapse survival significantly explains the dismal longterm survival of patients with AML. 4,8 In several studies investigators point to a role for lymphocytes, such as cytotoxic T cells and natural killer (NK) cells, in the surveillance of the malignant clone in AML and in determining prognosis. 9 T cells are considered to mediate the graft-versusleukemia reaction that significantly accounts for the reduced rate of leukemic relapse after allogeneic stem cell transplantation, 10,11 and several tumor-associated antigens of relevance to T-cell reactivity are expressed by AML cells. 12 A role for NK cells in surveillance of AML cells was demonstrated, as exemplified by the favorable outcome when authors used transplants with donor/recipient class I disparities, which facilitates NK cell-mediated destruction of residual leukemic cells. 13 In addition, multiple deficiencies of T-and NK-cell functions, with ensuing relapse risk and poor prognosis, have been observed in patients with AML who did not undergo transplantation. [14][15][16][17][18] In earlier studies, investigators demonstrated that nonmalignant phagocytic cells down-modulate lymphocyte functions by producing and releasing NADPH oxidase-derived reactive oxygen species (ROS). [19][20][21][22][23] These findings have formed the basis for the use of a NADPH oxidase inhibitor in conjunction with IL-2 as a relapsepreventive strategy in patients with AML. 24,25 In this study, we monitored the surface expression of gp91 phox , a component of the ROS-generating NADPH oxidase, 26 on leukemic cells recovered from BM and blood of newly diagnosed patients with AML and explored whether ROS produced by leukemic cells compromise Tand NK-cell function. These analyses were performed with cells recovered from patients with defined morphologic subtypes of AML cells on the basis of French-American-British (FAB) classification. 27 We report that AML cells from patients with monocytic forms of AML (FAB classes M4/M5), but not cells from patients with myeloblastic AML (FAB class M2) or immature AML (FAB class M1), express the NADPH oxidase, produce ROS, and trigger extensive apoptosis in adjacent T and NK cells. Our results are suggestive of a novel mechanism of immune evasion in myelomonocytic and monocytic AML. Methods Sampling of BM and peripheral bloodPeripheral blood or BM from 26 untreated...

Streptococcus pneumoniae is a major pathogen in humans. The pathogenicity of this organism is related to its many virulence factors, the most important of which is the thick pneumococcal capsule that minimizes phagocytosis. Another virulence-associated trait is the tendency of this bacterium to undergo autolysis in stationary phase through activation of the cell wall-bound amidase LytA, which breaks down peptidoglycan. The exact function of autolysis in pneumococcal pathogenesis is, however, unclear. Here, we show the selective and specific inefficiency of wild-type S. pneumoniae for inducing production of phagocyte-activating cytokines in human peripheral blood mononuclear cells (PBMC). Indeed, clinical pneumococcal strains induced production of 30-fold less tumor necrosis factor (TNF), 15-fold less gamma interferon (IFN-␥), and only negligible amounts of interleukin-12 (IL-12) compared with other closely related Streptococcus species, whereas the levels of induction of IL-6, IL-8, and IL-10 production were similar. If pneumococcal LytA was inactivated by mutation or by culture in a medium containing excess choline, the pneumococci induced production of significantly more TNF, IFN-␥, and IL-12 in PBMC, whereas the production of IL-6, IL-8, and IL-10 was unaffected. Further, adding autolyzed pneumococci to intact bacteria inhibited production of TNF, IFN-␥, and IL-12 in a dose-dependent manner but did not inhibit production of IL-6, IL-8, and IL-10 in response to the intact bacteria. Fragments from autolyzed bacteria inhibited phagocytosis of intact bacteria and reduced the in vitro elimination of pneumococci from human blood. Our results suggest that fragments generated by autolysis of bacteria with reduced viability interfere with phagocyte-mediated elimination of live pneumococci.

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