Enzymatic Inactivation of Oxysterols in Breast Tumor Cells Constraints Metastasis Formation by Reprogramming the Metastatic Lung Microenvironment

Recent evidence indicates that immune cells contribute to the formation of tumor metastases by regulating the pre-metastatic niche. Whether tumor-derived factors involved in primary tumor formation play a role in metastasis formation is poorly characterized. Oxysterols act as endogenous regulators of lipid metabolism through the interaction with the nuclear Liver X Receptors-(LXR)alpha and LXR beta. In the context of tumor development, they establish a pro-tumor environment by dampening antitumor immune responses, and by recruiting pro-angiogenic and immunosuppressive neutrophils. However, the ability of LXR/oxysterol axis to promote tumor invasion and metastasis by exploiting immune cells, is still up to debate. In this study we provide evidence that oxysterols participate in the primary growth of orthotopically implanted 4T1 breast tumors by establishing a tumor-promoting microenvironment. Furthermore, we show that oxysterols are involved in the metastatic spread of 4T1 breast tumors, since their enzymatic inactivation mediated by the sulfotransferase 2B1b, reduces the number of metastatic cells in the lungs of tumor-bearing mice. Finally, we provide evidence that oxysterols support the metastatic cascade by modifying the lung metastatic niche, particularly allowing the recruitment of tumor-promoting neutrophils. These results identify a possible new metastatic pathway to target in order to prevent metastasis formation in breast cancer patients

Prolonged contact with dendritic cells turns lymph node‐resident NK cells into anti‐tumor effectors

Abstract Natural killer (NK) cells are critical players against tumors. The outcome of anti‐tumor vaccination protocols depends on the efficiency of NK‐cell activation, and efforts are constantly made to manipulate them for immunotherapeutic approaches. Thus, a better understanding of NK‐cell activation dynamics is needed. NK‐cell interactions with accessory cells and trafficking between secondary lymphoid organs and tumoral tissues remain poorly characterized. Here, we show that upon triggering innate immunity with lipopolysaccharide (LPS), NK cells are transiently activated, leave the lymph node, and infiltrate the tumor, delaying its growth. Interestingly, NK cells are not actively recruited at the draining lymph node early after LPS administration, but continue their regular homeostatic turnover. Therefore, NK cells resident in the lymph node at the time of LPS administration become activated and exert anti‐tumor functions. NK‐cell activation correlates with the establishment of prolonged interactions with dendritic cells (DCs) in lymph nodes, as observed by two‐photon microscopy. Close DC and NK‐cell contacts are essential for the localized delivery of DC‐derived IL‐18 to NK cells, a strict requirement in NK‐cell activation

Pathology tissue–chromatin immunoprecipitation, coupled with high-throughput sequencing, allows the epigenetic profiling of patient samples

Epigenetic alterations in the pattern of DNA and histone modifications play a crucial role in cancer development. Analysis of patient samples, however, is hampered by technical limitations in the study of chromatin structure from pathology archives that usually consist of heavily fixed, paraffin-embedded material. Here, we present a methodology [pathology tissue–ChIP (PAT-ChIP)] to extract and immunoprecipitate chromatin from paraffin-embedded patient samples up to several years old. In a pairwise comparison with canonical ChIP, PAT-ChIP showed a high reproducibility of results for several histone marks and an identical ability to detect dynamic changes in chromatin structure upon pharmacological treatment. Finally, we showed that PAT-ChIP can be coupled with high-throughput sequencing (PAT-ChIP-Seq) for the genome-wide analysis of distinct chromatin modifications. PAT-ChIP therefore represents a versatile procedure and diagnostic tool for the analysis of epigenetic alterations in cancer and potentially other diseases

Combined liver and hematopoietic stem cell transplantation in patients with X-linked hyper-IgM syndrome

Liver disease in X-linked hyper IgM syndrome (XHIGM) is an important predictor of mortality. In case liver transplantation (LT) is required, a survival benefit is observed when LT is combined with HSCT.status: publishe

Stem cells, tissue engineering and periodontal regeneration

The aim of this review is to discuss the clinical utility of stem cells in periodontal regeneration by reviewing relevant literature that assesses the periodontal-regenerative potential of stem cells. We consider and describe the main stem cell populations that have been utilized with regard to periodontal regeneration, including bone marrow-derived mesenchymal stem cells and the main dental-derived mesenchymal stem cell populations: periodontal ligament stem cells, dental pulp stem cells, stem cells from human exfoliated deciduous teeth, stem cells from apical papilla and dental follicle precursor cells. Research into the use of stem cells for tissue regeneration has the potential to significantly influence periodontal treatment strategies in the future.J Han, D Menicanin, S Gronthos, and PM Bartol

Plasmacytoid dendritic cells and cancer.

Cancer develops in a complex microenvironment comprising cancer cells, stromal cells, and host immune cells with their soluble products. The counteracting host-protective and tumor-promoting roles of different immune cell populations have been elegantly clarified in the last decade by pertinent genetically modified mouse models. Among cells with a potential role in cancer immunity, PDCs might represent important players as a result of their capacity to bring together innate and adaptive immunity. This review summarizes current knowledge about the role of PDCs in cancer immunity. PDCs have been documented in primary and metastatic human neoplasms; however, the clinical significance of this finding is still unknown. Once into the tumor bed, PDCs can be hijacked by the tumor microenvironment and lose their propensity to produce the required amount of endogenous I-IFN. However, when properly reprogrammed (i.e., by TLR agonists), PDCs might mediate tumor rejection in a clinical setting. Tumor rejection, at least partially, is driven by I-IFN and seems to require a cross-talk with other innate immune cells, including IFN DCs. The latter evidence, although still limited to skin cancers, can provide a leading model for developing adjuvant immune therapy for other neoplasms. To this end, the generation of appropriate mouse models to modulate the frequency and activation state of murine PDCs will also be of remarkable importance