Quorum-sensing bacteria in a growing colony of cells send out signalling molecules (so-called “autoinducers”) and themselves sense the autoinducer concentration in their vicinity. Once—due to increased local cell density inside a “cluster” of the growing colony—the concentration of autoinducers exceeds a threshold value, cells in this clusters get “induced” into a communal, multi-cell biofilm-forming mode in a cluster-wide burst event. We analyse quantitatively the influence of spatial disorder, the local heterogeneity of the spatial distribution of cells in the colony, and additional physical parameters such as the autoinducer signal range on the induction dynamics of the cell colony. Spatial inhomogeneity with higher local cell concentrations in clusters leads to earlier but more localised induction events, while homogeneous distributions lead to comparatively delayed but more concerted induction of the cell colony, and, thus, a behaviour close to the mean-field dynamics. We quantify the induction dynamics with quantifiers such as the time series of induction events and burst sizes, the grouping into induction families, and the mean autoinducer concentration levels. Consequences for different scenarios of biofilm growth are discussed, providing possible cues for biofilm control in both health care and biotechnology.
Neutrophils have been described as a phenotypically heterogeneous cell type that possess both pro- and anti-tumor properties. Recently, a subset of neutrophils isolated from the peripheral blood mononuclear cell (PBMC) fraction has been described in cancer patients. These low-density neutrophils (LDNs) show a heterogeneous maturation state and have been associated with pro-tumor properties in comparison to mature, high-density neutrophils (HDNs). However, additional studies are necessary to characterize this cell population. Here we show new surface markers that allow us to discriminate between LDNs and HDNs in non-small cell lung cancer (NSCLC) patients and assess their potential as diagnostic/prognostic tool. LDNs were highly enriched in NSCLC patients (median=20.4%, range 0.3-76.1%; n=26) but not in healthy individuals (median=0.3%, range 0.1-3.9%; n=14). Using a high-dimensional human cell surface marker screen, we identified 12 surface markers that were downregulated in LDNs when compared to HDNs, while 41 surface markers were upregulated in the LDN subset. Using flow cytometry, we confirmed overexpression of CD36, CD41, CD61 and CD226 in the LDN fraction. In summary, our data support the notion that LDNs are a unique neutrophil population and provide novel targets to clarify their role in tumor progression and their potential as diagnostic and therapeutic tool.
Monoacylglycerol lipase (MGL) expressed in cancer cells influences cancer pathogenesis but the role of MGL in the tumor microenvironment (TME) is less known. Using a syngeneic tumor model with KP cells (Kras LSL-G12D /p53 fl/fl ; from mouse lung adenocarcinoma), we investigated whether TME-expressed MGL plays a role in tumor growth of non-small cell lung cancer (NSCLC). In sections of human and experimental NSCLC, MGL was found in tumor cells and various cells of the TME including macrophages and stromal cells. Mice treated with the MGL inhibitor JZL184 as well as MGL knock-out (KO) mice exhibited a lower tumor burden than the controls. The reduction in tumor growth was accompanied by an increased number of CD8 + T cells and eosinophils. Naïve CD8 + T cells showed a shift toward more effector cells in MGL KOs and an increased expression of granzyme-B and interferon-γ, indicative of enhanced tumoricidal activity. 2-arachidonoyl glycerol (2-AG) was increased in tumors of MGL KO mice, and dose-dependently induced differentiation and migration of CD8 + T cells as well as migration and activation of eosinophils in vitro . Our results suggest that next to cancer cell-derived MGL, TME cells expressing MGL are responsible for maintaining a pro-tumorigenic environment in tumors of NSCLC.
The 'iceberg map of germline mutations in childhood cancers' was created to increase the awareness of the inborn genetic underpinnings of childhood malignancies and their relationships with immunodeficiencies. Needs and perspectives of clinical immunologists and pediatric oncologists to both improve patient care and guide research at this critical interface are discussed. VIDEO ABSTRACT.
Myeloperoxidase (MPO) is a heme peroxidase that is mainly expressed and secreted by neutrophils. The role of MPO in inflammatory diseases has been highlighted in recent years, but its role in tumor development remains unclear. Therefore, we investigated the role of MPO in non-small cell lung cancer (NSCLC). In silico analysis revealed a survival benefit in patients with NSCLC and low MPO expression. Furthermore, a syngeneic tumor model using MPO knockout (KO) mice revealed that mice lacking MPO had lower tumor growth than controls. The reduction in tumor size was accompanied by an increase in lymphoid populations, including natural killer cells and CD8+ T cells, suggesting a shift to a more anti-tumorigenic immune environment in MPO-KO mouse tumors. The T cell induced interferon-gamma (IFN-γ) expression was increased in MPO- KO tumors, indicating increased tumoricidal activity. CD8 depletion abolished the previously observed reduction in tumor size in MPO-KO mice, indicating that CD8+ T cells play an important role. In vitro, T cells treated with MPO showed reduced proliferation and IFN-γ expression. Furthermore, MPO could be internalized into T cells. Heparin pretreatment of T cells blocked MPO binding and internalization into T cells and reversed MPO-induced proliferation reduction. Interestingly, MPO+ lymphocytes were found in tumor samples from patients with NSCLC. Our findings suggest that MPO plays an immunosuppressive role in NSCLC.
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