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.

CD40 ligand (CD40L), identified as a costimulatory molecule expressed on T cells, is also expressed and functional on platelets. We investigated the thrombotic and inflammatory contributions of platelet CD40L in atherosclerosis. Although CD40L-deficient (Cd40l ؊/؊ ) platelets exhibited impaired platelet aggregation and thrombus stability, the effects of platelet CD40L on inflammatory processes in atherosclerosis were more remarkable. Repeated injections of activated Cd40l ؊/؊ platelets into Apoe ؊/؊ mice strongly decreased both platelet and leukocyte adhesion to the endothelium and decreased plasma CCL2 levels compared with wildtype platelets. Moreover, Cd40l ؊/؊ platelets failed to form proinflammatory plateletleukocyte aggregates. Expression of CD40L on platelets was required for plateletinduced atherosclerosis as injection of Cd40l ؊/؊ platelets in contrast to Cd40l ؉/؉ platelets did not promote lesion formation. Remarkably, injection of Cd40l ؉/؉ , but not Cd40l ؊/؊ , platelets transiently decreased the amount of regulatory T cells