Biology subjects

Marwitz, S.

Publications and source records attributed to Marwitz, S..

4 recordsLinked to original sources

bioRxiv2024

Ablation of B cell-derived IL-10 increases tuberculosis resistance

Due to the historical dogma, that host defense against intracellular pathogens is mediated by cell-mediated immunity, B cells have been considered unimportant in providing protection against Mycobacterium tuberculosis (Mtb) and remained understudied for decades. However, emerging evidence suggests a more complex and multifaceted role for B cells in tuberculosis (TB) immunity. They accumulate at the side of infection in both animal models and human TB patients, suggesting a potential link to protective immunity. Still, the diverse roles of B cells in TB immunity continue to be unraveled. Apart from antibodies, B cells produce a wide range of cytokines, which can influence the local immune response. Here we addressed the relevance of interleukin 10 (IL-10) secreting B cells in long-term control of the Mtb Beijing strain HN878. Our research highlights the previously unknown role of B cell-derived IL-10 as a negative regulator of protective immunity in TB. For the first time, we demonstrate that mice lacking B cell-derived IL-10 show increased resistance to aerosol Mtb infection, as evidenced by a delayed onset of clinical symptoms and prolonged survival. Notably, this effect was significantly more pronounced in males compared to females, and was accompanied by male-specific immune alterations, indicating a previously unknown sex-specific regulatory role of B cell-derived IL-10 during Mtb infection.

immunology↗

bioRxiv2023

Glycodelin acts as an immunomodulator in NSCLC and is a predictor of poor prognosis for patients receiving immunotherapy

Lung cancer has been shown to be targetable by novel immunotherapies which reactivate the immune system and enable tumor cell killing. However, treatment failure and resistance to these therapies is common. Consideration of sex as a factor influencing therapy resistance is still rare. We hypothesize that the success of the treatment is impaired by the presence of the immunosuppressive pregnancy-associated glycoprotein glycodelin that is expressed in patients with non-small-cell lung cancer (NSCLC). We demonstrate that the glycan pattern of NSCLC-derived glycodelin detected by a lectin-based enrichment assay highly resembles amniotic fluid-derived glycodelin A, which is known to have immunosuppressive properties. NSCLC-derived glycodelin interacts with immune cells in vitro and regulates the expression of genes associated with inflammatory and tumor microenvironment pathways. In tumor microarray samples of patients, high glycodelin staining in tumor areas results in an impaired overall survival of female patients. Moreover, glycodelin colocalizes to tumor infiltrating CD8+ T cells and pro-tumorigenic M2 macrophages. High serum concentrations of glycodelin prior to immunotherapy are associated with a poor progression-free survival (p < 0.001) of female patients receiving PD-(L)1 inhibitors. In summary, our findings suggest that glycodelin not only is a promising immunological biomarker for early identification of female patients that do not benefit from the costly immunotherapy, but also represents a promising immunotherapeutic target in NSCLC to improve therapeutic options in lung cancer. BackgroundImmunotherapy is one of the major achievements in the last decade of lung cancer treatment. However, resistance to treatment is common und not well understood. Glycodelin is an immunosuppressive protein well described during the establishment of a pregnancy. We investigated its influence on immune cells and patients receiving immunotherapy with a focus on the sex of the patients. Translational relevanceOur study examined that NSCLC-derived glycodelin shares similarities to amniotic fluid-derived glycodelin A and is predictive for a worse response to immunotherapy in female patients. Therefore, glycodelin might be a key player influencing a sex-specific response to immunotherapy in lung cancer.

cancer biology↗

bioRxiv2021

Immune-evasion of KRAS-mutant lung adenocarcinoma mediated by cAMP response element-binding protein

cAMP response element-binding protein (CREB) mediates proliferative and inflammatory gene transcription in neurodegeneration and cancer, but its role in malignant immune-evasion of lung adenocarcinoma (LUAD) is unknown. We show that human LUAD of smokers are frequently altered along the CREB pathway and we employ mouse models to discover that KRAS-mutant LUAD co- opt CREB to evade immune rejection by tumoricidal neutrophils. For this, KRAS- driven CREB activation suppresses CXC-chemokine expression and prevents recruitment of CXCR1+ neutrophils. CREB1 is shown to be pro-tumorigenic in five different LUAD models, a function that is dependent on host CXCR1. Pharmacologic CREB blockade prevents tumor growth and restores neutrophil recruitment only when initiated before immune-evasion of KRAS-mutant LUAD. CREB and CXCR1 expression in human LUAD are compartmentalized to tumor and stromal cells, respectively, while CREB-regulated genes and neutrophils impact survival. In summary, CREB-mediated immune evasion of KRAS-mutant LUAD relies on signaling to neutrophil CXCR1 and is actionable.

cancer biology↗

bioRxiv2020

WNT6-ACC2-induced accumulation of triacylglycerol rich lipid droplets is exploited by Mycobacterium tuberculosis

In view of emerging drug-resistant tuberculosis, host directed therapies are urgently needed to improve treatment outcomes with currently available anti-tuberculosis therapies. One option is to interfere with the formation of lipid-laden “foamy” macrophages in the infected host. Here, we provide evidence that WNT6, a member of the evolutionary conserved WNT signaling pathway, promotes foam cell formation by regulating key lipid metabolic genes including acetyl-CoA carboxylase-2 (ACC2) during pulmonary TB. In addition, we demonstrate that Mycobacterium tuberculosis (Mtb) facilitates its intracellular growth and dissemination in the host by exploiting the WNT6-ACC2 pathway. Using genetic and pharmacological approaches, we show that lack of functional WNT6 or ACC2 significantly reduces intracellular TAG levels, Mtb growth and necrotic cell death of macrophages. In combination with the anti-TB drug isoniazid, pharmacological inhibition of ACC2 improved anti-mycobacterial treatment in vitro and in vivo. Therefore, we propose the WNT6-ACC2 signaling pathway as a promising target for a host-directed therapy to reduce intracellular replication of Mtb by modulating neutral lipid metabolism.Competing Interest StatementDrs. N. Reiling and J. Brandenburg (Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany) have filed a patent application entitled ACC inhibitors as means and methods for treating mycobacterial diseases(WO2018007430A1, patent pending).View Full Text

immunology↗