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(51) International Patent Classification: (21) International Application Number: (84) Designated States (Unless Otherwise Indica

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(51) International Patent Classification: (21) International Application Number: (84) Designated States (Unless Otherwise Indica ( (51) International Patent Classification: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, Not classified SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. (21) International Application Number: PCT/EP2020/053906 (84) Designated States (unless otherwise indicated, for every kind of regional protection available) . ARIPO (BW, GH, (22) International Filing Date: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, 14 February 2020 (14.02.2020) UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (25) Filing Language: English TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (26) Publication Language: English MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (30) Priority Data: TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, 19305197.6 18 February 2019 (18.02.2019) EP KM, ML, MR, NE, SN, TD, TG). (71) Applicants: INSERM (INSTITUT NATIONAL DE Published: LA SANTE ET DE LA RECHERCHE MEDICALE) — without international search report and to be republished [FR/FR]; 101, rue de Tolbiac, 75013 Paris (FR). upon receipt of that report (Rule 48. 2(g)) UNIVERSITE D'AIX MARSEILLE [FR/FR]; 58 Boule¬ — with sequence listing part of description (Rule 5.2(a)) vard Charles Livon, 13284 Marseille Cedex 07 (FR). CENTRE NATIONAL DE LA RECHERCHE SCIEN- TIFIQUE (CNRS) [FR/FR]; 3, Rue Michel Ange, 75016 Paris (FR). (72) Inventors: LAWRENCE, Toby; Kings College London - CIBCI/lst Floor, New Flunt's House Guy's Campus, Great Maze Pond, London SE1 1UL (GB). GOOSSENS, Pieter; Maastricht University Medical Center -, MUMC+ Depart¬ ment of Pathology -, P. Debyelaan 25, 6229HX Maas¬ tricht (NL). RODRIGUEZ VITA, Juan; DKFZ - Vascular signalling and cancer, (A270) Im Neuenheimer Feld 280, 69120 Heidelberg (DE). (74) Agent: INSERM TRANSFERT; 7 rue Watt, 75013 Paris (FR). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (54) Title: METHODS OF INDUCING PHENOTYPIC CHANGES IN MACROPHAGES (57) Abstract: Tumor-associated macrophages (TAM) have been shown to have important roles in the malignant progression of various cancers. However, macrophages also possess intrinsic tumoricidal activity and can promote the activity of cytotoxic lymphocytes, but they rapidly adopt an alternative phenotype within tumors, associated with immune-suppression and trophic functions that support tumor growth. The mechanisms that promote TAM polarization in the tumor-microenvironment 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 the inventors have characterized TAM in a mouse model of metastatic ovarian cancer. They show that ovarian cancer cells promote membrane-cholesterol efflux and the 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 tumor-induced membrane-cholesterol efflux in driving the IL-4 signaling and the tumor-promoting functions of TAM, while rendering them refractory to pro-inflammatory stimuli. Thus, preventing cholesterol efflux in TAM could represent a novel therapeutic strategy to block pro¬ tumor functions and restore anti-tumor immunity. WO 2020/169472 PCT/EP2020/053906 METHODS OF INDUCING PHENOTYPIC CHANGES IN MACROPHAGES FIELD OF THE INVENTION: The field of the invention is immunology. BACKGROUND OF THE INVENTION: There is now a wealth of clinical and experimental evidence that strongly links tumor- associated macrophages (TAM) with tumor progression, invasion and metastasis (Noy and Pollard, 2014). In the vast majority of published studies, increased numbers of TAM correlate with poor prognosis, but in some cases, specific TAM subsets have been associated with beneficial outcomes (de Vos van Steenwijk et a , 2013; Ino et al., 2013). Indeed, macrophages have been shown to posses intrinsic tumoricidal activity and promote the activation of cytotoxic lymphocytes (Bonnotte et al., 2001; Hagemann et al., 2008; Mytar et al., 1999), but they rapidly adopt an alternative phenotype within tumors, associated with immune-suppression and trophic functions that support tumor growth (Mantovani et al, 2008). However, the mechanisms that promote TAM reprogramming in the tumor-microenvironment remain poorly understood. In mammals, macrophages are found in all tissues after birth and are endowed with trophic functions that contribute to organ development and remodelling (Pollard, 2009). Recent advances in genetic fate-mapping techniques have revealed that the majority of tissue-resident macrophages, at least in steady-state, develop from embryonic precursors and are maintained by local proliferation with little input from hematopoeitc stem cells (HSC) in the bone marrow (Schulz et al., 2012). Subsequent studies have shown that embryonic macrophages can be gradually replaced by HSC-derived blood monocytes, to varying degrees depending on the specific context (Ginhoux and Guilliams, 2016). But the functional implications of these distinct developmental origins and certainly their respective contributions to tumor progression remain unclear. In a recent study, both tissue-resident macrophages of embryonic origin and monocyte-derived TAM were shown to contribute towards tumor growth in a mouse model of pancreatic cancer (Zhu et al., 2017). The phenotype of tissue-resident macrophages is dictated by the tissue-specific signals in their respective niche (Gosselin et al, 2014; Lavin et al., 2014). However, during inflammation or tissue stress, monocyte-derived macrophages can be recruited into tissues and their functional reprogramming is dictated by the pathological context. It is now widely appreciated that macrophages follow a multi-dimensional model of activation states with WO 2020/169472 PCT/EP2020/053906 distinct phenotypic and functional properties in response to different stimuli in the tissue microenvironment and can maintain considerable plasticity (Murray et al, 2014; Xue et al., 2014). Along these lines, TAM in various experimental models and human cancers have been shown to express uniques sets of gene patterns including the production of specific chemokines, cytokines and growth factors linked with tumor progression, such as CCL2, T , VEGF, basic fibroblast growth factor (bFGF) and matrix metalloproteinases (MMPs) (Kratochvill et al., 2015). Nevertheless, TAM are invariably reprogrammed towards a functional state that supports tumor growth and immune-suppression and away from inflammatory phenotypes that could be associated with anti-tumor functions. The specific mechanisms that drive TAM accumulation and polarization in different tumors remain unclear. Several studies have shown that TAM are CSF-1 dependent, as are most tissue macrophages, and CSF-1 signaling has been suggested to be an important factor in their reprogramming towards pro-tumor functions (Martinez et al., 2006; Noy and Pollard, 2014). CSF-1 and IL-4 signaling in TAM was later shown to cooperatively promote growth of lung metastatses in the MMTV-pyMT mouse model of mammary carcinonogenesis (DeNardo et al, 2009). However, although primary tumor- development in this model was CSF-1 dependent (Lin et al., 2006), IL-4 signaling in TAM did not impact primary tumors (DeNardo et al, 2009). Subsequent studies showed that the development of lung metastases, but not primary tumors, in the same model critically requires the recruitment of CCR2-dependent monocytes (Qian et al., 201 1). Suggesting that IL-4 signaling, specifically in monocyte-derived TAM, promotes metastatic disease in this model. SUMMARY OF THE INVENTION: As defined by the claims, the present relates to a method of inducing a phenotypic change in a population of macrophages in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agent that modulates cholesterol efflux in said population of macrophages. DETAILED DESCRIPTION OF THE INVENTION: Tumor-associated macrophages (TAM) have been shown to have important roles in the malignant progression of various cancers. However, macrophages also possess intrinsic tumoricidal activity and can promote the activity of cytotoxic lymphocytes, but they rapidly adopt an alternative phenotype within tumors, associated with immune-suppression and trophic functions that support tumor growth. The mechanisms that promote TAM polarization in the tumor-microenvironment remain poorly understood, these mechanisms may represent WO 2020/169472 PCT/EP2020/053906 important therapeutic targets to block the tumor-promoting functions of TAM and restore their anti-tumor potential. Here the inventors have characterized TAM in a mouse model of metastatic ovarian cancer. They show that ovarian cancer cells promote membrane-cholesterol efflux and the depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4 mediated reprogramming while inhibiting IFNy-induced gene expression. These studies reveal an unexpected role for tumor-induced membrane-cholesterol efflux in driving the IL-4 signaling
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