Breast cancer affects one in eight women in their lifetime. Though diet, age and genetic predisposition are established risk factors, the majority of breast cancers have unknown etiology. The human microbiota refers to the collection of microbes inhabiting the human body. Imbalance in microbial communities, or microbial dysbiosis, has been implicated in various human diseases including obesity, diabetes, and colon cancer. Therefore, we investigated the potential role of microbiota in breast cancer by next-generation sequencing using breast tumor tissue and paired normal adjacent tissue from the same patient. In a qualitative survey of the breast microbiota DNA, we found that the bacterium Methylobacterium radiotolerans is relatively enriched in tumor tissue, while the bacterium Sphingomonas yanoikuyae is relatively enriched in paired normal tissue. The relative abundances of these two bacterial species were inversely correlated in paired normal breast tissue but not in tumor tissue, indicating that dysbiosis is associated with breast cancer. Furthermore, the total bacterial DNA load was reduced in tumor versus paired normal and healthy breast tissue as determined by quantitative PCR. Interestingly, bacterial DNA load correlated inversely with advanced disease, a finding that could have broad implications in diagnosis and staging of breast cancer. Lastly, we observed lower basal levels of antibacterial response gene expression in tumor versus healthy breast tissue. Taken together, these data indicate that microbial DNA is present in the breast and that bacteria or their components may influence the local immune microenvironment. Our findings suggest a previously unrecognized link between dysbiosis and breast cancer which has potential diagnostic and therapeutic implications.

Neutrophil abscess formation is critical in innate immunity against many pathogens. Here, the mechanism of neutrophil abscess formation was investigated using a mouse model of Staphylococcus aureus cutaneous infection. Gene expression analysis and in vivo multispectral noninvasive imaging during the S. aureus infection revealed a strong functional and temporal association between neutrophil recruitment and IL-1β/IL-1R activation. Unexpectedly, neutrophils but not monocytes/macrophages or other MHCII-expressing antigen presenting cells were the predominant source of IL-1β at the site of infection. Furthermore, neutrophil-derived IL-1β was essential for host defense since adoptive transfer of IL-1β-expressing neutrophils was sufficient to restore the impaired neutrophil abscess formation in S. aureus-infected IL-1β-deficient mice. S. aureus-induced IL-1β production by neutrophils required TLR2, NOD2, FPR1 and the ASC/NLRP3 inflammasome in an α-toxin-dependent mechanism. Taken together, IL-1β and neutrophil abscess formation during an infection are functionally, temporally and spatially linked as a consequence of direct IL-1β production by neutrophils.

The anti-CD20 antibody rituximab has substantially improved outcomes in patients with B-cell non-Hodgkin lymphomas. However, many patients are not cured by rituximab-based therapies, and overcoming de novo or acquired rituximab resistance remains an important challenge to successful treatment of Bcell malignancies. Interferon-alpha (IFN␣) has potent immunostimulatory properties and antiproliferative effects against some B-cell cancers, but its clinical utility is limited by systemic toxicity. To improve the efficacy of CD20-targeted therapy, we constructed fusion proteins consisting of anti-CD20 and murine or human IFN␣. Fusion proteins had reduced IFN␣ activity in vitro compared with native IFN␣, but CD20 targeting permitted efficient antiproliferative and proapoptotic effects against an aggressive rituximab-insensitive human CD20 ؉ murine lymphoma (38C13-huCD20) and a human B-cell lymphoma (Daudi). In vivo efficacy was demonstrated against established 38C13-huCD20 grown in syngeneic immunocom- IntroductionThe anti-CD20 antibody rituximab (C2B8/Rituxan; Genentech/ Biogen-IDEC) has substantially improved treatment outcomes in B-cell non-Hodgkin lymphomas (NHLs), achieving high response rates in low-grade B-cell lymphomas, 1 and improving survival in both indolent and aggressive lymphomas in combination with chemotherapy. 2,3 However, many tumors do not respond to or relapse after rituximab-based therapies. 4 Thus, new approaches are needed to improve anti-CD20 efficacy and overcome rituximab resistance.The in vivo antilymphoma effects of rituximab are believed to be mediated by antibody dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), induction of apoptosis in tumor cells, and recruitment of T cells responding to tumor antigens released upon antibody-mediated tumor lysis. [5][6][7] Clinical studies have suggested that ADCC plays a dominant role in rituximab action in humans. 8,9 Thus, attempts have been made to boost rituximab-mediated ADCC by activation of Fc receptorbearing natural killer (NK) cells, monocytes/macrophages, or granulocytes via systemic administration of cytokines such as interleukin-2, interleukin-12, or granulocyte-macrophage colonystimulating factor, 10-12 with limited efficacy. None of these trials involving systemic administration of cytokines offered a clear advantage over the expected efficacy of rituximab alone, likely due to the inability of systemically administered agents to achieve high concentrations within the tumor bed.Interferon-alpha (IFN␣), a member of the type I interferon family (␣, ␤, ), is a pleiotropic cytokine with attractive features for combination with rituximab in treating NHL. 13,14 Beneficial properties of IFN␣ against NHL and other cancers include direct antiproliferative and proapoptotic effects, 15-17 blockade of autocrine growth factor loops, 18 repression of c-myc oncogene expression, 19 down-regulation of telomerase activity, 20 and inhibition of angiogenesis. 21 Favorable immunologic effects of IFN␣ for lymphoma treatment...

Staphylococcus aureus colonization is a major risk factor for infection. In this issue, Simanski et al. demonstrate that the antimicrobial peptide RNase 7 is essential for preventing S. aureus colonization in human skin. These findings suggest that therapeutic interventions aimed at targeting RNase 7 production in the skin may be a novel strategy to protect against S. aureus infections.

The anti-CD20 antibody rituximab has substantially improved outcomes in patients with B-cell non-Hodgkin lymphomas. However, many patients are not cured by rituximab-based therapies, and overcoming de novo or acquired rituximab resistance remains an important challenge to successful treatment of B-cell malignancies. Interferon alpha (IFNα) has potent immunostimulatory properties and anti-proliferative effects against some B-cell cancers, but its clinical utility is limited by systemic toxicity. To improve the efficacy of CD20-targeted therapy, we constructed fusion proteins consisting of anti-CD20 and murine or human IFNα. Fusion proteins had reduced IFNα activity in vitro compared with native IFNα, but CD20 targeting permitted efficient anti-proliferative and pro-apoptotic effects against an aggressive rituximab-insensitive human CD20+ murine lymphoma (38C13-huCD20) and a human B-cell lymphoma (Daudi). In vivo efficacy was demonstrated against established 38C13-huCD20 grown in syngeneic immunocompetent mice and large, established Daudi xenografts grown in nude mice. Optimal tumor eradication required CD20 targeting, with 87% of mice cured of rituximab-insensitive tumors. Gene knockdown studies revealed that tumor eradication required expression of type I IFN receptors on the tumor cell surface. Targeting type I IFNs to sites of B-cell lymphoma by fusion to anti-CD20 antibodies represents a potentially useful strategy for treatment of B-cell malignancies.

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