Biology subjects

Kancheva, D.

Publications and source records attributed to Kancheva, D..

4 recordsLinked to original sources

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↗

bioRxiv2023

Murine classical monocyte subsets display distinct functions and fates

Monocytes are short-lived myeloid immune cells that arise from adult hematopoiesis and circulate for a short time in the blood. They comprise two main subsets, in mice defined as classical Ly6Chigh and non-classical Ly6Clow monocytes (CM, NCM). Recent fate mapping and transcriptomic analyses revealed that CM themselves are heterogeneous. Here, we report surface markers that allow segregation of murine GMP- and MDP-derived CM in the BM and blood. Functional characterization, including fate definition following adoptive cell transfer, established that GMP-Mo and MDP-Mo could equal rise to homeostatic CM progeny, such as NCM in blood and gut macrophages, but differentially seeded selected other tissues. Specifically, GMP-Mo and MDP-Mo gave rise to distinct interstitial lung macrophages, thus linking CM dichotomy to previously reported pulmonary macrophage heterogeneity. Collectively, we provide comprehensive evidence for the existence of two functionally distinct CM subsets in the mouse, which differentially contribute to peripheral tissue macrophage populations in homeostasis and following challenge. Our findings are indicative of impact of monocyte ontogeny on in situ differentiation.

immunology↗

bioRxiv2022

Global hypo-methylation in a subgroup of glioblastoma enriched for an astrocytic signature is associated with increased invasion and altered immune landscape

We describe a new molecular subgroup of glioblastoma, the most prevalent malignant adult brain tumour, harbouring a bias towards hypomethylation at defined differentially methylated regions. This epigenetic signature correlates with an enrichment for an astrocytic gene signature, which together with the identification of enriched predicted binding sites of transcription factors known to cause demethylation and to be involved in astrocytic/glial lineage specification, point to a shared ontogeny between this glioblastoma subgroup and astroglial progenitors. At functional level, increased invasiveness, at least in part mediated by SRPX2, and macrophage infiltration characterise this glioblastoma subgroup.

cancer biology↗

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↗