Endothelial Rbpj is essential for the education of tumour-associated macrophages

Abstract

Epithelial ovarian cancer (EOC) is one of the most lethal gynaecological cancers worldwide. EOC cells educate tumour-associated macrophages (TAMs) through CD44-mediated cholesterol depletion to generate an immunosuppressive tumour microenvironment (TME). In addition, tumour cells frequently activate Notch1 receptors on endothelial cells (ECs) to facilitate metastasis. However, little is known whether the endothelium would also influence the education of recruited monocytes. Here, we report that canonical Notch signalling through RBPJ in ECs is an important player in the education of TAMs and EOC progression. Deletion of Rbpj in the endothelium of adult mice reduced infiltration of monocyte-derived macrophages into the TME of EOC and prevented the acquisition of a typical TAM gene signature. This was associated with stronger cytotoxic activity of T cells and decreased tumour burden. Mechanistically, we identified CXCL2 as a novel Notch/RBPJ target gene. This angiocrine factor regulates the expression of CD44 on monocytes and subsequent cholesterol depletion of TAMs. Bioinformatic analysis of ovarian cancer patient data showed that increased CXCL2 expression is accompanied by higher expression of CD44 and TAM education. As such, EOC cells employ the tumour endothelium to secrete CXCL2 in order to facilitate an immunosuppressive microenvironment.

DNA methylation landscape of tumor‐associated macrophages reveals pathways, transcription factors and prognostic value relevant to triple‐negative breast cancer patients

“…Additionally, the hallmarks of epithelial to mesenchymal transition, Il6/JAK/STAT3, Tumor necrosis factor-alpha (TNF-α) signaling and Interferongamma (IFN-γ) response were enriched in cluster 4 and identified in the potentially BMDM-originating clusters 2 or 6. Cluster 1, hypomethylated in TAMs and BMDMs, was enriched for IL2/STAT5 and Notch signaling, validating its recently identified function in monocyte recruitment and TAM education 3,29. WNT-β catenin signaling was attributed to the TAM and BMDM hypermethylated cluster 3.Overall, these results show that the TAM methylome can be dissected into distinct epigenetic programs, linked to specific TFs and pathways, some unique to TAMs and others reminiscent of their proposed monocytic origin 2,4,10,11.…”