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Due to a combination of rapid disease progression and the lack of curative treatment options, hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. Infiltrated, monocyte-derived, tumor-associated macrophages are known to play a role in HCC pathogenesis, but the involvement of Kupffer cells (KCs) remains elusive. Here, we used the Clec4F-diphteria toxin receptor transgenic mouse model to specifically investigate the effect of KC depletion on HCC initiation, progression and neoplastic growth following liver resection. For this purpose, several HCC mouse models with varying underlying etiologies were used and partial hepatectomy was performed. Our results show that in HCC, developed on a fibrotic or non-alcoholic steatohepatitis background, depletion of embryonic KCs at the onset of HCC induction and the subsequent replacement by monocyte-derived KCs does not affect the tumor burden, tumor microenvironment or the phenotype of isolated KCs at end-stage disease. In non-chronic liver disease-associated diethylnitrosamine-induced HCC, ablation of Clec4F+ KCs did not alter tumor progression or neoplastic growth following liver resection. Our results show that temporal ablation of resident KCs does not impact HCC pathogenesis, neither in the induction phase nor in advanced disease, and indicate that bone marrow-derived KCs are able to swiftly repopulate the available KC niche and adopt their phenotype.

The stromal compartment of the tumor microenvironment consists of a heterogeneous set of tissue-resident and tumor-infiltrating cells, which are profoundly moulded by cancer cells. An outstanding question is to what extent this heterogeneity is similar between cancers affecting different organs. Here, we profile 233,591 single cells from patients with lung, colorectal, ovary and breast cancer (n = 36) and construct a pan-cancer blueprint of stromal cell heterogeneity using different single-cell RNA and protein-based technologies. We identify 68 stromal cell populations, of which 46 are shared between cancer types and 22 are unique. We also characterise each population phenotypically by highlighting its marker genes, transcription factors, metabolic activities and tissue-specific expression differences. Resident cell types are characterised by substantial tissue specificity, while tumor-infiltrating cell types are largely shared across cancer types. Finally, by applying the blueprint to melanoma tumors treated with checkpoint immunotherapy and identifying a naïve CD4+ T-cell phenotype predictive of response to checkpoint immunotherapy, we illustrate how it can serve as a guide to interpret scRNA-seq data. In conclusion, by providing a comprehensive blueprint through an interactive web server, we generate the first panoramic view on the shared complexity of stromal cells in different cancers. ispartof: CELL RESEARCH vol:30 issue:9 pages:745-762 ispartof: location:England status: published

Physiologic turnover of interstitial collagen is mediated by a sequential pathway in which collagen is fragmented by pericellular collagenases, endocytosed by collagen receptors, and routed to lysosomes for degradation by cathepsins. Here, we use intravital microscopy to investigate if malignant tumors, which are characterized by high rates of extracellular matrix turnover, utilize a similar collagen degradation pathway. Tumors of epithelial, mesenchymal, or neural crest origin all display vigorous endocytic collagen degradation. The cells engaged in this process are identified as tumor-associated macrophage (TAM)-like cells that degrade collagen in a mannose receptor-dependent manner. Accordingly, mannose-receptor-deficient mice display increased intratumoral collagen. Whole-transcriptome profiling uncovers a distinct extracellular matrix-catabolic signature of these collagen-degrading TAMs. Lineage-ablation studies reveal that collagen-degrading TAMs originate from circulating CCR2+ monocytes. This study identifies a function of TAMs in altering the tumor microenvironment through endocytic collagen turnover and establishes macrophages as centrally engaged in tumor-associated collagen degradation. Madsen et al. identify a population of tumor-associated macrophages with a distinct matrix catabolic signature as key effectors of collagen turnover during invasive tumor growth. These matrix-degrading macrophages are largely derived from CCR2+ monocytes reprogrammed by the tumor microenvironment and degrade collagen through mannose receptor-dependent cellular uptake.

Background Treatment with erythropoietin (Epo) in experimental autoimmune encephalomyelitis (EAE), the rodent model of multiple sclerosis (MS), has consistently been shown to ameliorate disease progression and improve overall outcome. The effect has been attributed to modulation of the immune response and/or preservation of the central nervous system (CNS) tissue integrity. It remains unclear, however, if (a) Epo acts primarily in the CNS or the periphery and if (b) Epo’s beneficial effect in EAE is mainly due to maintaining CNS tissue integrity or to modulation of the immune response. If Epo acts primarily by modulating the immune system, where is this modulation required? In the periphery, the CNS or both? Methods To address these questions, we used two well-characterized transgenic mouse strains that constitutively overexpress recombinant human Epo (rhEpo) either systemically (tg6) or in CNS only (tg21) in a MOG-induced EAE model. We assessed clinical severity, disease progression, immunomodulation, and CNS tissue integrity, including neuronal survival. Results Although disease onset remained unaffected, EAE progression was alleviated in transgenic animals compared to controls with both lines performing equally well showing that expression of Epo in the periphery is not required; Epo expression in the CNS is sufficient. Immunomodulation was observed in both strains but surprisingly the profile of modulation differed substantially between strains. Modulation in the tg21 strain was limited to a reduction in macrophages in the CNS, with no peripheral immunomodulatory effects observed. In contrast, in the tg6 strain, macrophages were upregulated in the CNS, and, in the periphery of this strain, T cells and macrophages were downregulated. The lack of a consistent immunomodulatory profile across both transgenic species suggests that immunomodulation by Epo is unlikely to be the primary mechanism driving amelioration of EAE. Finally, CNS tissue integrity was affected in all strains. Although myelin appeared equally damaged in all strains, neuronal survival was significantly improved in the spinal cord of tg21 mice, indicating that Epo may ameliorate EAE predominantly by protecting neurons. Conclusions Our data suggests that moderate elevated brain Epo levels provide clinically significant neuroprotection in EAE without modulation of the immune response making a significant contribution. Electronic supplementary material The online version of this article (10.1186/s12974-017-0976-5) contains supplementary material, which is available to authorized users.

Antiparasite responses are associated with the recruitment of monocytes that differentiate to macrophages and dendritic cells at the site of infection. Although classically activated monocytic cells are assumed to be the major source of TNF and NO during Trypanosoma brucei brucei infection, their cellular origin remains unclear. In this study, we show that bone marrow-derived monocytes accumulate and differentiate to TNF/inducible NO synthase-producing dendritic cells (TIP-DCs) in the spleen, liver, and lymph nodes of T. brucei brucei-infected mice. Although TIP-DCs have been shown to play a beneficial role in the elimination of several intracellular pathogens, we report that TIP-DCs, as a major source of TNF and NO in inflamed organs, could contribute actively to tissue damage during the chronic stage of T. brucei brucei infection. In addition, the absence of IL-10 leads to enhanced differentiation of monocytes to TIP-DCs, resulting in exacerbated pathogenicity and early death of the host. Finally, we demonstrate that sustained production of IL-10 following IL-10 gene delivery treatment with an adeno-associated viral vector to chronically infected mice limits the differentiation of monocytes to TIP-DCs and protects the host from tissue damage.

// Sarah Cattin 1 , Benoit Fellay 2 , Sylvain Pradervand 3 , Andreas Trojan 4 , Thomas Ruhstaller 5 , Curzio Ruegg 1, * , Gregor Furstenberger 6, * 1 Department of Medicine, Faculty of Science, University of Fribourg, CH-1700 Fribourg, Switzerland 2 Central Laboratory, HFR Hopital Cantonal, CH-1700 Fribourg, Switzerland 3 Genomic Technologies Facility, Center of Integrative Genomic (CIG), University of Lausanne (UNIL), CH-1015 Lausanne, Switzerland 4 OnkoZentrum Zurich, CH-8038 Zurich, Switzerland 5 Breast Center, Kantonsspital St.Gallen, CH-9000 St.Gallen, Switzerland 6 Tumor and Breast Center ZeTuP, CH-9006 St.Gallen, Switzerland * These authors have contributed equally to this work Correspondence to: Curzio Ruegg, e-mail: curzio.ruegg@unifr.ch Keywords: breast cancer, angiogenesis, monocytes, KIT, IL-10 Received: September 28, 2015 Accepted: January 18, 2016 Published: January 31, 2016 ABSTRACT Background: Whether bevacizumab exerts its anti-tumor properties through systemic effects beyond local inhibition of angiogenesis and how these effects can be monitored in patients, remain largely elusive. To address these questions, we investigated bone marrow-derived cells and cytokines in the peripheral blood of metastatic breast cancer patients undergoing therapy with bevacizumab. Methods: Circulating endothelial cells (CEC), circulating endothelial progenitor (CEP) and circulating CD11b + cells in metastatic breast cancer patients before and during therapy with paclitaxel alone ( n = 11) or in combination with bevacizumab ( n = 10) were characterized using flow cytometry, real time PCR and RNASeq. Circulating factors were measured by ELISA. Aged-matched healthy donors were used as baseline controls ( n = 12). Results: Breast cancer patients had elevated frequencies of CEC, CEP, TIE2+CD11b + and KIT + CD11b + cell subsets. CEC decreased during therapy, irrespective of bevacizumab, while TIE2 + CD11b + remained unchanged. KIT + CD11b + cells decreased in response to paclitaxel with bevacizumab, but not paclitaxel alone. Cancer patients expressed higher mRNA levels of the M2 polarization markers CD163, ARG1 and IL-10 in CD11b + cells and increased levels of the M2 cytokines IL-10 and CCL20 in plasma. M1 activation markers and cytokines were low or equally expressed in cancer patients compared to healthy donors. Chemotherapy with paclitaxel and bevacizumab, but not with paclitaxel alone, significantly decreased IL-10 mRNA in CD11b + cells and IL-10 protein in plasma. Conclusions: This pilot study provides evidence of systemic immunomodulatory effects of bevacizumab and identified circulating KIT + CD11b + cells and IL-10 as candidate biomarkers of bevacizumab activity in metastatic breast cancer patients.

Objective— Although junctional adhesion molecule (JAM)-C has been implicated in the control of inflammatory leukocyte recruitment, its role in neointima formation after arterial injury has not been elucidated. Methods and Results— In apolipoprotein E–deficient ( Apoe −/− ) mice fed an atherogenic diet, antibody blockade of JAM-C significantly reduced neointimal hyperplasia after wire injury of carotid arteries without altering medial area and decreased neointimal macrophage but not smooth muscle cell (SMC) content. An increased expression of JAM-C was detected in colocalization with luminal SMCs 1 day after injury and neointimal SMCs after 3 weeks. Blocking JAM-C inhibited monocytic cell arrest and leukocyte adhesion to carotid arteries perfused ex vivo and in vivo. Furthermore, monocyte adhesion to activated coronary artery SMCs under flow conditions in vitro was diminished by blocking JAM-C. Conclusions— Our data provide the first evidence for a crucial role of JAM-C in accelerated lesion formation and leukocyte recruitment in atherosclerosis-prone mice.

Antiparasite responses are associated with the recruitment of monocytes that differentiate to macrophages and dendritic cells at the site of infection. Although classically activated monocytic cells are assumed to be the major source of TNF and NO during Trypanosoma brucei brucei infection, their cellular origin remains unclear. In this study, we show that bone marrow-derived monocytes accumulate and differentiate to TNF/inducible NO synthase-producing dendritic cells (TIP-DCs) in the spleen, liver, and lymph nodes of T. brucei brucei-infected mice. Although TIP-DCs have been shown to play a beneficial role in the elimination of several intracellular pathogens, we report that TIP-DCs, as a major source of TNF and NO in inflamed organs, could contribute actively to tissue damage during the chronic stage of T. brucei brucei infection. In addition, the absence of IL-10 leads to enhanced differentiation of monocytes to TIP-DCs, resulting in exacerbated pathogenicity and early death of the host. Finally, we demonstrate that sustained production of IL-10 following IL-10 gene delivery treatment with an adeno-associated viral vector to chronically infected mice limits the differentiation of monocytes to TIP-DCs and protects the host from tissue damage.

Background—Lipopolysaccharide (LPS), which is released from Gram-negative bacteria on multiplication or lysis, aggravates atherosclerosis in humans and rodents by inducing inflammation via toll-like receptors. Because apolipoprotein C-I (apoCI) enhances the LPS-induced inflammatory response in macrophages in vitro and in mice, we investigated the effect of endogenous apoCI expression on LPS-induced atherosclerosis in mice.Methods and Results—Twelve-week-oldapoe−/−apoc1−/−andapoe−/−apoc1+/+mice received weekly intraperitoneal injections of LPS (50 μg) or vehicle for a period of 10 weeks, and atherosclerosis development was assessed in the aortic root. LPS administration did not affect atherosclerotic lesion area inapoe−/−apoc1−/−mice but increased it inapoe−/−apoc1+/+mice. In fact, apoCI expression increased the LPS-induced atherosclerotic lesion area by 60% (PConclusions—We conclude that apoCI is crucially involved in LPS-induced atherosclerosis inapoe−/−mice, which mainly relates to an increased inflammatory response toward LPS. We anticipate that apoCI plasma levels contribute to accelerated atherosclerosis development in individuals who have chronic infection.