Biology subjects

Elkrim, Y.

Publications and source records attributed to Elkrim, Y..

4 recordsLinked to original sources

bioRxiv2024

VSIG4-Expressing Macrophages Contribute To Anti-Parasitic And Anti-Metastatic Responses In The Peritoneal Cavity

Peritoneal tissue-resident macrophages, also referred to as large peritoneal macrophages (LPMs), play an important role as gatekeepers of peritoneal homeostasis by providing a first line of defense against pathogenic threats. About a third of the LPMs express the surface receptor V-set and Immunoglobulin domain containing 4 (VSIG4), but it is unclear to what extent these cells differ from their VSIG4-negative counterparts and perform dedicated functions. Here, we demonstrate that VSIG4+ LPMs, in contrast to VSIG4- LPMs, are in majority derived from embryonal precursors and their occurrence is to a large extent independent from sex and microbiota. Although their transcriptome and surface proteome are indistinguishable from VSIG4- LPMs at steady-state, VSIG4+ LPMs are superior in phagocytosing Gram-positive bacteria and colorectal carcinoma (CRC) cells. In-house generated anti-VSIG4 nanobody constructs that are antibody-dependent cell-mediated cytotoxicity (ADCC)-enabled allowed a selective elimination of the VSIG4+ LPM subset without affecting the overall LPM content of the peritoneal cavity. This strategy uncovered a role for VSIG4+ LPMs in lowering the first peak of parasitemia in a Trypanosoma brucei brucei infection model and in reducing the outgrowth of CRC cells in the peritoneal cavity, a prime metastatic site in CRC patients. Altogether, our data uncover a protective role for VSIG4+ LPMs in infectious and oncological diseases in the peritoneal cavity.

immunology↗

bioRxiv2024

Epigenomic programming of peripheral monocytes determines their transcriptional response to the tumor microenvironment

Classical monocytes are recruited to tumors and undergo transcriptional reprogramming resulting in tumor-promoting functions. Epigenomic features, such as post-translational modification of histones and chromatin accessibility, are key determinants of transcription factor binding and thereby play an important role in determining transcriptional responses to the tissue environment. It is unknown to what extent the epigenetic landscape of peripheral monocytes is rewired by cancer and how this could shape their transcriptional response upon recruitment to the tumor microenvironment. Here we used a combination of genome-wide assays for mRNA expression, chromatin accessibility and multiple histone modifications (H3K4me1, H3K4me3, H3K27ac) in a mouse model to investigate changes in the epigenomic landscape of peripheral monocytes. We then linked these epigenetic alterations to gene expression changes in monocytes occurring in the periphery or during tumor infiltration. We found that the distal tumor caused extensive remodeling of both H3K4me3+ promoters and H3K4me1+ enhancers in peripheral monocytes. Specifically, this involved the repression of interferon-responsive promoters and enhancers as well as the establishment of enhancers harboring binding motifs for transcription factors downstream of inflammatory and cytokine signaling pathways. The enhancers altered in the periphery could be linked to sustained gene expression changes which were less likely to be reversed in the tumor microenvironment. In addition, genes activated upon tumor infiltration showed prior epigenetic priming in peripheral monocytes. Overall, these results indicate that the epigenomic landscape of peripheral monocytes is altered in response to a distal tumor, and this could shape the transcriptional response of monocytes when they encounter microenvironmental signals upon infiltrating the tumor.

immunology↗

bioRxiv2021

Distinct cDC subsets co-operate in CD40 agonist response while suppressive microenvironments and lack of antigens subvert efficacy

Agonistic CD40 therapy has shown to inhibit cancer progression, but only in a fraction of patients. Hence, understanding the cancer cell-intrinsic and microenvironmental determinants of CD40 therapy response is crucial to identify responsive patient populations and design efficient combination treatments. Here, we showed that the therapeutic efficacy of CD40 in responder melanoma tumours, relied on pre-existing cDC1-primed CD8+ T cells, however cDC1s were dispensable after CD40 administration. Surprisingly, in response to CD40 the abundance of activated cDCs, potentially derived from cDC2s increased, thereby further activating antitumour CD8+ T cells. Hence, distinct cDC subsets are required to induce CD40 responses. By contrast, lung tumours, characterised by a high abundance of macrophages, were resistant to CD40 therapy. Combining CD40 therapy with macrophage depletion led to tumour growth inhibition only in the presence of strong neoantigens. Accordingly, treatment with immunogenic cell-death inducing chemotherapy sensitised non-immunogenic tumours to CD40 therapy.

cancer biology↗

bioRxiv2020

Inflammasome- and gasdermin D-independent IL-1β production mobilizes neutrophils to inhibit antitumor immunity

Interleukin-1{beta} (IL-1{beta}) is a central mediator of inflammation whose secretion typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL-1{beta} in promoting cancer progression in patients, but the underlying mechanisms are little understood. Here, we show a key role for IL-1{beta} in driving tumor progression in two distinct mouse tumor models. Notably, inflammasome activation and GSDMD were dispensable for the production of intratumoral bioactive IL-1{beta}, which promoted systemic mobilization and infiltration of neutrophils into tumors. Neutrophils recruited via IL-1{beta} suppressed the acquisition of an effector T-cell phenotype and subsequent antitumor immune response. Moreover, IL-1{beta} was essential for neutrophil accumulation upon antiangiogenic therapy, thereby contributing to therapy-induced immunosuppression. Antitumor immunity in the absence of IL-1{beta}-dependent neutrophil recruitment relied on immunostimulatory macrophages which promoted the infiltration and activation of cytotoxic T-cells. Overall, these results support a tumor-promoting role for IL-1{beta} through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for its release in tumors.

immunology↗