Journal Article

DKFZ-2022-03003

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Endothelial RBPJ Is Essential for the Education of Tumor-Associated Macrophages.

Alsina-Sanchis, E. (First author)DKFZ* ; Mülfarth, R. (First author)DKFZ* ; Moll, I.DKFZ* ; Böhn, S. V.DKFZ* ; Wiedmann, L.DKFZ* ; Jordana-Urriza, L.DKFZ* ; Ziegelbauer, T.DKFZ* ; Zimmer, E.DKFZ* ; Taylor, J.DKFZ* ; De Angelis Rigotti, F.DKFZ* ; Stögbauer, A.DKFZ* ; Giaimo, B. D. ; Cerwenka, A. ; Borggrefe, T. ; Fischer, A. (Last author)DKFZ* ; Rodriguez-Vita, J. (Last author)DKFZ*

2022
AACR Philadelphia, Pa.

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Please use a persistent id in citations: doi:10.1158/0008-5472.CAN-22-0076

Abstract: Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic cancers worldwide. EOC cells educate tumor-associated macrophages (TAM) through CD44-mediated cholesterol depletion to generate an immunosuppressive tumor microenvironment (TME). In addition, tumor cells frequently activate Notch1 receptors on endothelial cells (EC) to facilitate metastasis. However, further work is required to establish whether the endothelium also influences the education of recruited monocytes. Here, we report that canonical Notch signaling 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 tumor burden. Mechanistically, CXCL2 was identified as a novel Notch/RBPJ target gene that regulated 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. Together, these findings indicate that EOC cells induce the tumor endothelium to secrete CXCL2 to establish an immunosuppressive microenvironment.Endothelial Notch signaling favors immunosuppression by increasing CXCL2 secretion to stimulate CD44 expression in macrophages, facilitating their education by tumor cells.

Keyword(s): Humans (MeSH) ; Female (MeSH) ; Mice (MeSH) ; Animals (MeSH) ; Tumor-Associated Macrophages (MeSH) ; Endothelial Cells: pathology (MeSH) ; Carcinoma, Ovarian Epithelial: genetics (MeSH) ; Ovarian Neoplasms: pathology (MeSH) ; Tumor Microenvironment (MeSH) ; Endothelium: metabolism (MeSH) ; Cholesterol (MeSH) ; Immunoglobulin J Recombination Signal Sequence-Binding Protein: genetics (MeSH) ; Cholesterol ; RBPJ protein, human ; Immunoglobulin J Recombination Signal Sequence-Binding Protein ; Rbpj protein, mouse

Note: #EA:A270#LA:A270#

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Contributing Institute(s):

1. A270 Vaskuläre Signaltransduktion und Krebs (A270)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2022

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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