Biology subjects

Voronov, E.

Publications and source records attributed to Voronov, E..

3 recordsLinked to original sources

bioRxiv2023

Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1β

Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the inflammasome and the release of the proinflammatory cytokine interleukin 1{beta} (IL-1{beta}). However, the role of IL-1{beta} in intestinal defense against Salmonella remains unclear. Here, we show that IL-1{beta} production is detrimental during Salmonella infection. Mice lacking IL-1{beta} (IL-1{beta} -/-) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid-producing commensals. Changes in epithelial cell metabolism that typically support pathogen expansion, such as switching energy production from fatty acid oxidation to fermentation, were absent in infected IL-1{beta}-/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1{beta} induces expression of complement anaphylatoxins and suppresses the complement-inactivator Carboxypeptidase N (CPN1). Disrupting this process via IL-1{beta} loss completely prevented mortality in Salmonella-infected IL-1{beta}-/- mice and led to chronic infection. Thus, Salmonella exploits IL-1{beta} signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1{beta} signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.

immunology↗

bioRxiv2021

IL-1α secreted by subcapsular sinus macrophages promotes melanoma metastasis in the sentinel lymph node by upregulating STAT3 signaling in the tumor.

During melanoma metastasization, tumor cells originated in the skin migrate via lymphatic vessels to the sentinel lymph node (sLN) in a process that facilitates their spread across the body. Here, we characterized the innate inflammatory responses to melanoma metastasis in the sLN. For this purpose, we confirmed the migration of fluorescent metastatic melanoma cells to the sLN and we characterized the inflammatory response in the metastatic microenvironment. We found that macrophages located in the subcapsular sinus (SSM), produce pro-tumoral IL-1 after recognition of tumor antigens. Moreover, we confirmed that the administration of an anti-IL-1 depleting antibody reduced metastasis. Conversely, the administration of recombinant IL-1 accelerated the lymphatic spreading of the tumor. Additionally, the elimination of the macrophages significantly reduced the progression of the metastatic spread. To understand the mechanism of action of IL-1 in the context of the lymph node microenvironment, we applied single-cell RNA sequencing to dissected metastases obtained from animals treated with an anti-IL-1 blocking antibody. Amongst the different pathways affected, we identified STAT3 as one of the main targets of IL-1 signaling in metastatic cells. Moreover, we found that the anti-IL-1 anti-tumoral effect was not mediated by lymphocytes, as IL-1R1 KO mice did not show any improvement in metastasis growth. Finally, we found a synergistic anti-metastatic effect of the combination of IL-1 blocking and the STAT3 inhibitor (STAT3i) stattic. In summary, we described a new mechanism by which SSM support melanoma metastasis, highlighting a new target for immunotherapy.

immunology↗

bioRxiv2021

MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer

Although the mitogen-activated protein kinases (MAPK) pathway is hyperactive in head and neck cancer (HNC), inhibition of MEK1/2 in HNC patients has not shown clinically meaningful activity. Using pre-clinical HNC models, we demonstrated that treatment with the MEK1/2 blocker trametinib delays HNC initiation and progression by reducing tumor cell proliferation and enhancing the anti-tumor immunity of CD8+ T cells. Further activation of CD8+ T cells by supplementation with anti-programmed death-1 (PD-1) antibody eliminated tumors and induced an immune memory in the cured mice. Mechanistically, an early response to trametinib treatment sensitized tumors to PD-1-supplementation by attenuating the expression of tumor-derived colony-stimulating factor-1 (CSF-1), which reduced the abundance of two CSF-1R+CD11c+ myeloid-derived suppressor cell (MDSC) populations in the tumor microenvironment (TME). In contrast, prolonged treatment with trametinib abolished the anti-tumor activity of PD-1, because tumor cells undergoing the epithelial to mesenchymal transition (EMT) in response to trametinib restored CSF-1 expression and re-created an immune-suppressive TME. These findings provide the rationale for testing the trametinib/PD-1 combination in HNC and highlight the importance of sensitizing tumors to immunotherapies by using targeted therapies to interfere with the host-tumor interaction. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/457244v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1c65286org.highwire.dtl.DTLVardef@1541becorg.highwire.dtl.DTLVardef@f557f3org.highwire.dtl.DTLVardef@16134dc_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

cancer biology↗