Human BDCA3+ dendritic cells (DCs) were suggested to be homologous to mouse CD8α+ DCs. We demonstrate that human BDCA3+ DCs are more efficient than their BDCA1+ counterparts or plasmacytoid DCs (pDCs) in cross-presenting antigen and activating CD8+ T cells, which is similar to mouse CD8α+ DCs as compared with CD11b+ DCs or pDCs, although with more moderate differences between human DC subsets. Yet, no specific marker was known to be shared between homologous DC subsets across species. We found that XC chemokine receptor 1 (XCR1) is specifically expressed and active in mouse CD8α+, human BDCA3+, and sheep CD26+ DCs and is conserved across species. The mRNA encoding the XCR1 ligand chemokine (C motif) ligand 1 (XCL1) is selectively expressed in natural killer (NK) and CD8+ T lymphocytes at steady-state and is enhanced upon activation. Moreover, the Xcl1 mRNA is selectively expressed at high levels in central memory compared with naive CD8+ T lymphocytes. Finally, XCR1−/− mice have decreased early CD8+ T cell responses to Listeria monocytogenes infection, which is associated with higher bacterial loads early in infection. Therefore, XCR1 constitutes the first conserved specific marker for cell subsets homologous to mouse CD8α+ DCs in higher vertebrates and promotes their ability to activate early CD8+ T cell defenses against an intracellular pathogenic bacteria.

Highlights  Monocyte-derived TAM gradually replace resident peritoneal macrophages in metastatic ovarian cancer  Ovarian cancer cells promote membrane-cholesterol efflux in TAM  Cholesterol-efflux depletes lipid rafts and increases IL-4 signaling in TAM  Inhibition of ABC transporters reverts the tumor-promoting functions of TAM in ovarian cancer eTOC blurb Goossens et al. show that cancer cells scavenge membrane cholesterol from macrophages in tumors which reprogrammes them towards an immune-suppressive and tumor-promoting phenotype and makes them resistant to activation by anti-tumor cytokines. SummaryTumor-associated macrophages (TAM) have been shown to have important roles in the malignant progression of various cancers. However, macrophages also posses intrinsic tumoricidal activity, but rapidly adopt an alternative phenotype within tumors associated with immune-suppression and trophic functions supporting tumor growth. The mechanisms that promote TAM polarization remain poorly understood, these mechanisms may represent important therapeutic targets to block the tumor-promoting functions of TAM and restore their anti-tumor potential. Here we have characterized TAM in a mouse model of metastatic ovarian cancer. We show that ovarian cancer cells promote membrane-cholesterol efflux and depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4 mediated reprogramming while inhibiting IFN-induced gene expression. These studies reveal an unexpected role for membrane-cholesterol efflux in driving the tumor-promoting functions of TAM, while rendering them refractory to pro-inflammatory stimuli. Thus, preventing cholesterol efflux in TAM may represent a novel therapeutic strategy to block pro-tumor functions and restore anti-tumor immunity.