BackgroundSorafenib is the only approved first line systemic therapy for advanced hepatocellular carcinoma (HCC) in the last decade. Tumour resistance to sorafenib has been of major obstacles to improve HCC patient survival.MethodsWe polarised THP-1 cells to M1 and M2 macrophages, performed various in vitro assays and developed sorafenib-resistant xenograft models to investigate the role of tumour-associated macrophages (TAM)-secreted molecules in HCC resistance to the targeted therapy.ResultsWe demonstrated M2, but not M1, macrophages not only promote proliferation, colony formation and migration of hepatoma cells but also significantly confer tumour resistance to sorafenib via sustaining tumour growth and metastasis by secreting hepatocyte growth factor (HGF). HGF activates HGF/c-Met, ERK1/2/MAPK and PI3K/AKT pathways in tumour cells. Tumour-associated M2 macrophages were accumulated in sorafenib-resistance tumours more than in sorafenib-sensitive tumours in vivo and produced abundant HGF. HGF chemoattracts more macrophages migrated from surrounding area, regulates the distribution of M2 macrophages and increases hepatoma resistance to sorafenib in a feed-forward manner.ConclusionsOur results provide new insights into the mechanisms of sorafenib resistance in HCC and rationale for developing new trials by combining sorafenib with a potent HGF inhibitor such as cabozantinib to improve the first line systemic therapeutic efficacy.

Dendritic cells play important roles in regulating innate and adaptive immune responses. DEC205 (CD205) is one of the major endocytotic receptors on dendritic cells and has been widely used for vaccine generation against viruses and tumors. However, little is known about its structure and functional mechanism. Here we determine the structure of the human DEC205 ectodomain by cryoelectron microscopy. The structure shows that the 12 extracellular domains form a compact double ring-shaped conformation at acidic pH and become extended at basic pH. Biochemical data indicate that the pHdependent conformational change of DEC205 is correlated with ligand binding and release. DEC205 only binds to apoptotic and necrotic cells at acidic pH, whereas live cells cannot be recognized by DEC205 at either acidic or basic conditions. These results suggest that DEC205 is an immune receptor that recognizes apoptotic and necrotic cells specifically through a pH-dependent mechanism.DEC205 | pH dependence | apoptosis | cryoEM | mannose receptor family I n living organisms such as humans, billions of cells are turned over through apoptosis or killed by pathological infections or inflammation every day. Therefore, clearance of dead cells is critical for maintaining tissue homeostasis and preventing autoimmunity and inflammation (1-3). Dead cells are usually removed by the host immune system through phagocytosis by phagocytes. Antigen-presenting cells (APCs) such as dendritic cells and macrophages are professional phagocytes that can engulf target cells or fragments by recognizing specific ligands through their cell surface receptors (4), and after antigen uptake, processing, and presentation, they can lead to either immune activation or tolerance (5-8).DEC205 (CD205 or Ly75, MW 205 kDa) is an endocytotic receptor with wide tissue distribution and is highly expressed on dendritic cells and thymic epithelial cells (8,9). It has been shown that DEC205 is involved in antigen uptake and can induce either tolerance or immunity in the absence or presence of inflammatory stimulus (10). It has also been suggested that DEC205 may bind apoptotic and necrotic cells (11) and oligonucleotides (12); however, neither the structure nor the functional mechanism of DEC205 has been identified.In contrast, the role of DEC205 in generating protective immunity has been studied extensively. It is probably the most widely used receptor target in dendritic cell-based immune therapies. The high efficiency of antigen delivery and presentation makes DEC205 an ideal vehicle for vaccine generation against various antigens such as tumors and viruses (13, 14), mainly through DEC205-specific antibodies fused with a fragment or intact protein of the target antigen (15-17). This strategy has been shown to be successful in generate protective immune responses and reveals good potentials in clinical applications (18). DEC205 belongs to the mannose receptor family (19). To date, five proteins have been classified as the mannose receptor family members, including the mannose ...

Melanoma is one of the most aggressive skin cancers worldwide. Although there has been much effort toward improving treatment options over the past few years, there remains an urgent need for effective therapy. Immunotherapy combined with chemotherapy has shown great promise in clinical trials. Here, we studied the cooperative effects of the small molecule drug pimozide, which has a therapeutic effect in melanoma, and RNA interference (RNAi) targeting PD-1, an important immune checkpoint molecule involved in tumor immune escape. PD-1 siRNA was delivered by attenuated Salmonella to melanoma-bearing mice in combination with pimozide. Our results demonstrated that the combination therapy had the optimal therapeutic effect on melanoma. The mechanisms underlying the efficacy involved the induction of apoptosis and an enhanced immune response. This study suggests that immunotherapy based on PD-1 inhibition combined with anticancer drugs could be a promising clinical strategy for the treatment of melanoma.