A phase I trial of NK-92 cells for refractory hematological malignancies relapsing after autologous hematopoietic cell transplantation shows safety and evidence of efficacy A phase I trial of NK-92 cells for refractory hematological malignancies relapsing after autologous hematopoietic cell transplantation shows safety and evidence of efficacy

Although adipocytes are the most abundant stromal cell component in breast cancer tissues, their interaction with breast cancer cells has been less investigated compared to cancer-associated fibroblasts or macrophages. Exosomes are a novel way of cell-cell communication and have been demonstrated to play an important role in various biological processes. However, to our knowledge, only a few studies have reported the effects of adipocyte exosomes on tumor development. Here, utilizing exosomes isolated from in vitro mesenchymal stromal/stem cell (MSC)-differentiated adipocytes, we systematically investigated this issue in a breast cancer model. Exosomes were isolated from MSC-differentiated adipocytes and added to breast cancer cells MCF7. Cell proliferation was detected by MTS, and migration was analyzed by wound healing and transwell assay. An in vivo mouse xenograft model was used to evaluate MSC-differentiated adipocyte exosomes’ contribution to tumor growth. Signaling pathway activation was evaluated by western blot and immunofluorescence staining. We found MSC-differentiated adipocyte-derived exosomes are actively incorporated by breast cancer cell MCF7 and subsequently promote MCF7 proliferation and migration as well as protect MCF7 from serum derivation or chemotherapeutic drug-induced apoptosis in vitro. In the in vivo mouse xenograft model, depletion of exosomes reduces tumor-promoting effects of adipocytes. Transcriptomic analysis of MSC-differentiated adipocyte exosome-treated MCF7 identified several activated signaling pathways, among which we confirm the Hippo signaling pathway and found a blockade of this pathway leads to a reduced growth-promoting effect of adipocyte exosomes. Taken together, our findings provide new insights into the role of adipocyte exosomes in the tumor microenvironment.

The initiation and progression of hepatocellular carcinoma (HCC) are largely dependent on its local microenvironment. Adipocytes are an important component of hepatic microenvironment in nonalcoholic fatty liver disease (NAFLD), which is a significant risk factor for HCC. Given the global prevalence of NAFLD, a better understanding of the interplay between HCC cells and adipocytes is urgently needed. Exosomes, released by malignant cells, represent a novel way of cell-cell interaction and have been shown to play an important role in cancer cell communication with their microenvironment. Here, we explore the role of HCC-derived exosomes in the cellular and molecular conversion of adipocytes into tumor-promoting cells. Exosomes were isolated from HCC cell line HepG2 and added to adipocytes. Transcriptomic alterations of exosome-stimulated adipocytes were analyzed using gene expression profiling, and secretion of inflammation-associated cytokines was detected by RT-PCR and ELISA. In vivo mouse xenograft model was used to evaluate the growth-promoting and angiogenesis-enhancing effects of exosome-treated adipocytes. Protein content of tumor exosomes was analyzed by mass spectrometry. Activated phospho-kinases involved in exosome-treated adipocytes were detected by phospho-kinase antibody array and Western blot. Our results demonstrated that HCC cell HepG2-derived exosomes could be actively internalized by adipocytes and caused significant transcriptomic alterations and in particular induced an inflammatory phenotype in adipocytes. The tumor exosome-treated adipocytes, named exo-adipocytes, promoted tumor growth, enhanced angiogenesis, and recruited more macrophages in mouse xenograft model. In vitro, conditioned medium from exo-adipocytes promoted HepG2 cell migration and increased tube formation of human umbilical vein endothelial cells (HUVECs). Mechanistically, we found HepG2 exosomes activated several phopho-kinases and NF-κB signaling pathway in exo-adipocytes. Additionally, a total of 1428 proteins were identified in HepG2 exosomes by mass spectrometry. Our results provide new insights into the concept that tumor cell-derived exosomes can educate surrounding adipocytes to create a favorable microenvironment for tumor progression.

Tremendous progress in treatment and outcomes has been achieved across the whole range of haematological malignancies in the past two decades. Although cure rates for aggressive malignancies have increased, nowhere has progress been more impactful than in the management of typically incurable forms of haematological cancer. Population-based data have shown that 5-year survival for patients with chronic myelogenous and chronic lymphocytic leukaemia, indolent B-cell lymphomas, and multiple myeloma has improved markedly. This improvement is a result of substantial changes in disease management strategies in these malignancies. Several haematological malignancies are now chronic diseases that are treated with continuously administered therapies that have unique side-effects over time. In this Commission, an international panel of clinicians, clinical investigators, methodologists, regulators, and patient advocates representing a broad range of academic and clinical cancer expertise examine adverse events in haematological malignancies. The issues pertaining to assessment of adverse events examined here are relevant to a range of malignancies and have been, to date, underexplored in the context of haematology. The aim of this Commission is to improve toxicity assessment in clinical trials in haematological malignancies by critically examining the current process of adverse event assessment, highlighting the need to incorporate patient-reported outcomes, addressing issues unique to stem-cell transplantation and survivorship, appraising challenges in regulatory approval, and evaluating toxicity in real-world patients. We have identified a range of priority issues in these areas and defined potential solutions to challenges associated with adverse event assessment in the current treatment landscape of haematological malignancies.

Mesenchymal stromal cells (MSCs) are the subject of numerous clinical trials, largely due to their immunomodulatory and tissue regenerative properties. Toll-like receptors (TLRs), especially TLR3 and TLR4, are highly expressed on MSCs and their activation can significantly modulate the immunosuppressive and anti-inflammatory functions of MSCs. While MSCs can recruit and promote the generation of regulatory T cells (Tregs), the effect of TLR activation on MSC-mediated Treg induction is unknown. In this study, we investigated the effect of ligand-mediated activation of TLR3 and TLR4 on Treg induction by human MSCs. We found that generation of Tregs in human CD4(+) lymphocyte and MSC cocultures was enhanced by either TLR3 or TLR4 activation of MSCs and that the increase was abolished by TLR3 and TLR4 gene-silencing. Augmented Treg induction by TLR-activated MSCs was cell contact-dependent and associated with increased gene expression of the Notch ligand, Delta-like 1. Moreover, inhibition of Notch signaling abrogated the augmented Treg levels in the MSC cocultures. Our data show that TLR3 or TLR4 activation of MSCs increases Treg induction via the Notch pathway and suggest new means to enhance the potency of MSCs for treating disorders with an underlying immune dysfunction, including steroid resistant acute graft-versus-host disease. Stem Cells 2016

Traditional uses of herbal medicine have depended mostly on anecdotal evidence for much of history. The increasing application of scientific rigor to the study some of these traditional therapies in recent years has revealed potent bioactivity, notably demonstrated by the 2015 Nobel Prize for the discovery of an anti-malarial compound from traditional Chinese herbs. Given the recent successes of immunotherapy and checkpoint blockade, there is a renewed interest in identifying new drugs with immunomodulatory effects. As an estimated 45-60% of cancer patients worldwide are reported to use complementary alternative medicine alongside traditional therapy, this review will highlight the literature on the immunomodulatory effects of one of these compounds. We report on the induction of a largely pro-inflammatory cytokine profile by the polysaccharopeptide (PSP) isolated from the Coriolus versicolor (Yun zhi) mushroom, as well as its effects on various immune subsets, and the clinical data that have led to its widespread adoption as an adjunct cancer therapeutic in many Eastern cultures. Particular focus is given to the potential mechanisms underlying the bioactivity of PSP and reports of its ability to promote antitumor immunity by helping overcome tolerogenic tumor microenvironments.