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International audience; Objectives: To investigate the role of cancer-associated fibroblasts (CAFs) in clear cell renal cell carcinoma (ccRCC) with respect to tumour aggressiveness, metastasis development, and resistance to anti-angiogenic therapy (vascular endothelial growth factor receptor-tyrosine kinase inhibitors [VEGFR-TKI]).Patients and methods: Our study involved tissue samples from three distinct and independent cohorts of patients with ccRCC. The presence of CAFs and tumour lymphangiogenesis was investigated, respectively, by transcriptional signatures and then correlated with tumour development and prognosis. The effect of these CAFs on tumour cell migration and VEGFR-TKI resistance was analysed on co-cultures of ccRCC cells with CAFs.Results: Results from our cohorts and from in silico investigations showed that VEGFR-TKI significantly increase the number of CAFs in tumours. In the same populations of patients with ccRCC, the proportion of intra-tumoral CAFs correlated to shorter disease-free and overall survival. The presence of CAFs was also correlated with lymphangiogenesis and lymph node metastasis. CAFs increased the migration and decreased the VEGFR-TKI-dependent cytotoxic effect of tumour cells.Conclusions: Our results show that VEGFR-TKI promote the development of CAFs, and CAFs favour tumour aggressiveness, metastatic dissemination, and resistance to treatment in ccRCC. CAFs could represent a new therapeutic target to fight resistance to treatment of ccRCC. Targeting CAF and immunotherapies combination are emerging as efficient treatments in many types of solid tumours. Our results highlight their relevance in ccRCC.

Local or metastatic relapse following surgery, radiotherapy, and cisplatin is the leading cause of death in patients with head and neck squamous cell carcinoma (HNSCC). Our study shows overexpression of c-MET and AXL in HNSCC cells and patients resistant to radiotherapy and cisplatin. We demonstrate that cabozantinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), c-MET, and AXL, decreases migration, invasion, and proliferation and induces mitotic catastrophe and apoptotic cell death of naive and radiotherapy- and cisplatin-resistant HNSCC cells. Cabozantinib inhibits the growth and metastatic spread of experimental HNSCC in zebrafish and the growth of experimental HNSCC in mice by blocking tumor cell proliferation and angiogenesis. The efficacy of cabozantinib is also confirmed on viable sections of surgically removed specimens of human HNSCC and on a patient who relapses after five lines of treatment. These results suggest that cabozantinib is relevant for the treatment of patients with HNSCC after relapse under radiotherapy and cisplatin.

Local or metastatic relapses following surgery, radiotherapy and chemotherapy (cisplatin) are the leading causes of death of patients with head and neck squamous cell carcinoma (HNSCC). In the current study, we showed that acquired resistance to radiotherapy and cisplatin of HNSCC cells and patients depends on overexpression of c-MET and AXL. Cabozantinib, a VEGFR, c-MET and AXL inhibitor, decreased migration, invasion and proliferation, and induced mitotic catastrophe and apoptotic cell death of naive and radiotherapy- and cisplatin-resistant HNSCC cells.Cabozantinib inhibited the growth of experimental HNSCC in mice by inhibiting tumor cell proliferation and angiogenesis. Cabozantinib inhibited the growth and the metastatic spread of experimental HNSCC in zebrafish. The efficacy of cabozantinib on experimental models of HNSCC was further confirmed on viable sections of surgically removed specimens of human HNSCC. These results suggest that cabozantinib is highly relevant for the treatment of HNSCC patients following relapses on radiotherapy and cisplatin.

Neovascular age-related macular degeneration (vAMD), characterized by the neo-vascularization of the retro-foveolar choroid, leads to blindness within few years. This disease depends on angiogenesis mediated by the vascular endothelial growth factor A (VEGF) and to inflammation. The only available treatments consist of monthly intravitreal injections of antibodies directed against VEGF or VEGF/VEGFB/PlGF decoy receptors. Despite their relative efficacy, these drugs only delay progression to blindness and 30% of the patients are insensitive to these treatments. Hence, new therapeutic strategies are urgently needed. Experimental models of vAMD are essential to screen different innovative therapeutics. The currently used in vitro and in vivo models in ophthalmic translational research and their relevance are discussed in this review.

Metastatic clear cell renal cell carcinoma (mccRCC) benefits from several treatment options in the first-line setting with VEGFR inhibitors and/or immunotherapy including anti-PD-L1 or anti-PD1 agents. Identification of predictive biomarkers is highly needed to optimize patient care. Circulating markers could reflect the biology of metastatic disease. Therefore, we evaluated soluble forms of PD-L1 (sPD-L1) and PD-1 (sPD-1) in mccRCC patients. The levels of sPD-L1 and sPD-1 were evaluated from plasma samples of mccRCC patients before they received a first-line treatment (T0) by the VEGFR inhibitor sunitinib (50 patients) or by the anti-VEGF bevacizumab (37 patients). The levels of sPD-L1 and sPD-1 were correlated to clinical parameters and progression-free survival (PFS). High levels of sPD-1 or sPDL1 were not correlated to PFS under bevacizumab while they were independent prognostic factors of PFS in the sunitinib group. Patients with high T0 plasmatic levels of sPD-L1 had a shorter PFS (11.3 vs 22.5 months, p = .011) in the sunitinib group. Equivalent shorter PFS was found with high levels of sPD-1 (8.6 vs 14.1 months, p = .009). mccRCC patients with high plasmatic levels of sPD-L1 or sPD-1 are poor responders to sunitinib. sPD-L1 or sPD-1 could be a valuable tool to guide the optimal treatment strategy including VEGFR inhibitor.

Macrophages possess intrinsic tumoricidal activity, yet tumor-associated macrophages (TAMs) rapidly adopt an alternative phenotype within the tumor microenvironment that is marked by tumor-promoting immunosuppressive and trophic functions. The mechanisms that promote such TAM polarization remain poorly understood, but once identified, they may represent important therapeutic targets to block the tumor-promoting functions of TAMs and restore their anti-tumor potential. Here, we have characterized TAMs 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, including inhibition of IFNγ-induced gene expression. Genetic deletion of ABC transporters, which mediate cholesterol efflux, reverts the tumor-promoting functions of TAMs and reduces tumor progression. These studies reveal an unexpected role for membrane-cholesterol efflux in driving TAM-mediated tumor progression while pointing to a potentially novel anti-tumor therapeutic strategy. Goossens, Rodriguez-Vita et al. show that cancer cells scavenge membrane cholesterol from tumor-associated macrophages, resulting in their reprogramming toward an immune-suppressive and tumor-promoting phenotype. Targeting cholesterol efflux in macrophages counters this reprogramming and reduces tumor progression in a model of ovarian cancer.

Tumor-associated macrophages (TAM) have been shown to have important roles in the malignant progression of various cancers. However, macrophages also posses 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 we have characterized TAM in a mouse model of metastatic ovarian cancer. We 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 IFNγ-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.

Conjugated polymer nanoparticles are being developed for a variety of diagnostic and theranostic applications. The conjugated polymer, F8BT, a polyfluorene derivative, was used as a model system to examine the biological behavior of conjugated polymer nanoparticle formulations stabilized with ionic (sodium dodecyl sulfate; F8BT-SDS; ∼207 nm; -31 mV) and nonionic (pegylated 12-hydroxystearate; F8BT-PEG; ∼175 nm; -5 mV) surfactants, and compared with polystyrene nanoparticles of a similar size (PS200; ∼217 nm; -40 mV). F8BT nanoparticles were as hydrophobic as PS200 (hydrophobic interaction chromatography index value: 0.96) and showed evidence of protein corona formation after incubation with serum-containing medium; however, unlike polystyrene, F8BT nanoparticles did not enrich specific proteins onto the nanoparticle surface. J774A.1 macrophage cells internalized approximately ∼20% and ∼60% of the F8BT-SDS and PS200 delivered dose (calculated by the ISDD model) in serum-supplemented and serum-free conditions, respectively, while cell association of F8BT-PEG was minimal (5% of the delivered dose). F8BT-PEG, however, was more cytotoxic (IC50 4.5 μg cm(-2)) than F8BT-SDS or PS200. The study results highlight that F8BT surface chemistry influences the composition of the protein corona, while the properties of the conjugated polymer nanoparticle surfactant stabilizer used determine particle internalization and biocompatibility profile.