Myeloid-derived suppressor cells (MDSC) are one of the major factors limiting the 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+ immunosuppressive MDSC in BM of patients with newly diagnosed MM. To assess the possible role of MDSC in MM, we used immunocompetent mouse models. Immunosuppressive MDSC accumulated in BM of mice as early as 1 wk 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 compared with wild-type mice. Growth of the immunogenic MM cells was significantly reduced in S100A9KO mice. This effect was associated with the accumulation of Ag-specific CD8+ T cells in BM and spleens of S100A9KO mice, but not wild-type mice, and was abrogated by the administration of anti-CD8 Ab or adoptive transfer of MDSC. Thus, the accumulation of MDSC at early stages of MM plays a critical role in MM progression and suggests that MDSC can be considered a possible therapeutic target in this disease.

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.

The epithelial-to-mesenchymal transition, which conveys epithelial (E) carcinoma cells to quasi-mesenchymal (qM) states, enables them to metastasize and acquire resistance to certain treatments. Murine tumors composed of qM mammary carcinoma cells assemble an immunosuppressive tumor microenvironment (TME) and develop resistance to anti-CTLA4 immune-checkpoint blockade (ICB) therapy, unlike their E counterparts. Importantly, minority populations of qM cells within a tumor can cross-protect their more E neighbors from immune attack. The underlying mechanisms of immunosuppression and cross-protection have been unclear. We demonstrate that abrogation of qM carcinoma cell–derived factors (CD73, CSF1, or SPP1) prevents the assembly of an immunosuppressive TME and sensitizes otherwise refractory qM tumors partially or completely to anti-CTLA4 ICB. Most strikingly, mixed tumors in which minority populations of carcinoma cells no longer express CD73 are now sensitized to anti-CTLA4 ICB. Finally, loss of CD73 also enhances the efficacy of anti-CTLA4 ICB during the process of metastatic colonization. Significance: Minority populations of qM carcinoma cells, which likely reside in human breast carcinomas, can cross-protect their E neighbors from immune attack. Understanding the mechanisms by which qM carcinoma cells resist antitumor immune attack can help identify signaling channels that can be interrupted to potentiate the efficacy of checkpoint blockade immunotherapies. This article is highlighted in the In This Issue feature, p. 995

Objectives To investigate the presumed acquisition of ampicillin resistance by an Escherichia coli strain residing in the gut of an infant.

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 IFNγ-producing NK cells into lungs of WT but not of Nox2-KO mice. IFNγ-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 IFNγ-dependent, NK cell–mediated clearance of melanoma cells. Cancer Immunol Res; 5(9); 804–11. ©2017 AACR.

Streptococcus pneumoniaeis 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 theS. pneumoniaestrains 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.