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 antimalarial 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
(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.
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 2017;35:265–275
Mesenchymal stromal cells (MSCs) promote the generation of regulatory T cells (Tregs). Toll‐like receptors (TLRs) are expressed by MSCs and can affect their phenotype upon activation. Here, we describe the effect of TLR3 and TLR4 activation on the induction of Tregs by MSCs. We show that preconditioning MSCs with TLR3 or TLR4 ligands enhances MSC‐mediated Treg induction. The augmentation is cell contact‐dependent and involves Notch signaling in coculture with CD4+ lymphocytes.
MSCs are widely applied to regenerate heart tissue in myocardial diseases but when grown in standard two-dimensional (2D) cultures exhibit limited potential for cardiac repair and develop fibrogenic ...features with increasing culture time. MSCs can undergo partial cardiomyogenic differentiation, which improves their cardiac repair capacity. When applied to collagen patches they may improve cardiac tissue regeneration but the mechanisms remain elusive. Here, we investigated the regenerative properties of MSCs grown in a collagen scaffold as a three-dimensional (3D) culture system, and performed functional analysis using an engineered heart tissue (EHT) model. We showed that the expression of cardiomyocyte-specific proteins by MSCs co-cultured with rat neonatal cardiomyocytes was increased in collagen patches versus conventional cultures. MSCs in 3D collagen patches were less fibrogenic, secreted more cardiotrophic factors, retained anti-apoptotic and immunomodulatory function, and responded less to TLR4 ligand lipopolysaccharide (LPS) stimulation. EHT analysis showed no effects by MSCs on cardiomyocyte function, whereas control dermal fibroblasts abrogated the beating of cardiac tissue constructs. We conclude that 3D collagen scaffold improves the cardioprotective effects of MSCs by enhancing the production of trophic factors and modifying their immune modulatory and fibrogenic phenotype. The improvement in myocardial function by MSCs after acquisition of a partial cardiac cell-like phenotype is not due to enhanced MSC contractility. A better understanding of the mechanisms of MSC-mediated tissue repair will help to further enhance the therapeutic potency of MSCs.
The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosis-inducing activity against various cells, especially tumor cells. Here, we present evidence ...that S100A8/A9 also has cell growth-promoting activity at low concentrations. Receptor of advanced glycation end product (RAGE) gene silencing and cotreatment with a RAGE-specific blocking antibody revealed that this activity was mediated via RAGE ligation. To investigate the signaling pathways, MAPK phosphorylation and NF-kappaB activation were characterized in S100A8/A9-treated cells. S100A8/A9 caused a significant increase in p38 MAPK and p44/42 kinase phosphorylation, and the status of stress-activated protein kinase/JNK phosphorylation remained unchanged. Treatment of cells with S100A8/A9 also enhanced NF-kappaB activation. RAGE small interfering RNA pretreatment abrogated the S100A8/A9-induced NF-kappaB activation. Our data indicate that S100A8/A9-promoted cell growth occurs through RAGE signaling and activation of NF-kappaB.
Mesenchymal stromal cells (MSCs) deploy Toll‐like receptors (TLRs) to respond to exogenous and endogenous signals. Activation of TLR pathways in MSCs alters their inflammatory profile and ...immunomodulatory effects on cells from both the innate and adaptive immune systems. Micro‐RNAs (miRNAs), whose expression is modulated by TLR activation, can regulate inflammatory responses by targeting components of the TLR signaling pathways either in MSCs or in the cells with which they interact. Here, we review how the miRNA‐TLR pathway axis can regulate the immunomodulatory functions of MSCs, including their interactions with monocytes/macrophages and natural killer cells, and discuss the therapeutic implications for MSC‐based therapies. Stem Cells 2018;36:1655–1662
TLR pathways‐microRNA interplay in MSCs affects the phenotype of MSCs and the interacting microenvironment including immune cells. TLR‐responding microRNA may also transfer to the new cells via extracellular vesicles released by MSCs.
Acquisition of a complex immune system during evolution provided organisms with the most effective defense mechanism against "foreign" or "non-self" invaders. This efficient protection against ...pathogens, however, has been achieved at the expense of a higher risk for "self reaction or autoimmunity. Establishment of self-tolerance and homeostasis in the immune system is regulated at different physiological stages of immune cells development. The breakdown in discrimination between "self" and "non-self"causes an aberrant immune response against autoantigens that promote damage to the "self" cells and tissue(s), resulting in various autoimmune phenotypes. Whereas activation and clonal proliferation of autoreactive T- and B- lymphocytes underlies the pathogenesis of autoimmune diseases, the mechanism by which self-tolerance is lost and autoimmune responses are induced is not clear yet. Autoimmunity is a multi-step process that occurs as a consequence of complex interaction between genetic susceptibility and non-genetic factors. Programmed cell death, as a key mechanism to regulate immune system function, has a crucial influence on both the selection process of immune cells and the maintenance of this immune tolerance in peripheral repertoire. Thus, defects in apoptotic death pathways may contribute to the development of autoimmune response in susceptible individuals in certain conditions.
BackgroundTreatment of recurrent/refractory (r/r) DLBCL remains an unmet clinical need, and new effective and well-tolerated treatments are required. DPX-Survivac is a unique T cell activation ...therapy that targets survivin-expressing tumor cells and has shown anti-tumor activity in clinical trials. This trial is evaluating a novel immunotherapy combination with DPX-Survivac, intermittent low dose CPA and pembrolizumab.Methods‘SPiReL’ is a Phase 2 non-randomized, open label, efficacy and safety study of a novel immunotherapy combination with DPX-Survivac (a unique T cell activation therapy that targets survivin-expressing tumor cells), intermittent low dose CPA and pembrolizumab, treatment regimen as described in figure 1. Subjects with r/r incurable DLBCL and survivin expression are eligible for participation. This study was approved by the Ontario Cancer Research Ethics Board, approval number 0981.ORR is assessed by modified Cheson criteria. For translational analyses, baseline and on-treatment PBMCs, along with tumor biopsy samples are collected from each subject. Survivin-specific systemic T cell responses are assessed using IFNγ-ELISPOT assay and tumour immune-infiltrate profile by multiplex-IHC.ResultsTwenty-two subjects have been enrolled to date, 19 are included in the intent to treat (ITT) population and 11 subjects are evaluable in the per protocol (PP) population. In the PP, the ORR is 63.6% including 3 CRs (27.3%), 4 PRs (36.4%) and the DCR is 81.8% (9/11). In the ITT, the ORR is 35% (7/19), and DCR is 52.0% (10/19). Preliminary results show that non-GCB subjects had a higher proportion of clinical response (4/8, 50%), compared to 3/10 (30%) in GCB subjects.DPX-Survivac-induced T cell responses were observed in 8/19 subjects (42.1%) including 6 subjects with clinical response (PR, CR), one SD and one PD. Multiplex-IHC analyses demonstrated baseline tumor PD-L1 expression in 6/7 subjects with a clinical response (85.7%, p<0.05). Similarly, subjects with higher baseline CD4+ and CD8+ T cell infiltration demonstrated a trend towards clinical response (table 1).Abstract 356 Figure 1SPiReL treatment regimenAbstract 356 Table 1Data summary of resultsConclusionsDPX-Survivac, intermittent low-dose CPA and pembrolizumab is generally well tolerated and can induce clinical responses in subjects with r/r DLBCL (7/11, 63.6% of evaluable subjects), including subjects with both non-GCB and GCB subtypes. Pre-treatment biopsies of clinical responders were characterized by higher baseline tumor PD-L1 expression and CD4 and CD8 infiltration. Extending this exploratory data in a larger cohort may define a r/r DLBCL patient population with a higher likelihood to respond to this novel combination immunotherapy.Trial RegistrationNCT03349450Ethics ApprovalThis study was approved by the Ontario Cancer Research Ethics Board, approval number 0981.
Despite decades of search for anticancer drugs targeting solid tumors, this group of diseases remains largely incurable, especially if in advanced, metastatic stage. In this review, we draw ...comparison between reprogramming and carcinogenesis, as well as between stem cells (SCs) and cancer stem cells (CSCs), focusing on changing garniture of adhesion molecules. Furthermore, we elaborate on the role of adhesion molecules in the regulation of (cancer) SCs division (symmetric or asymmetric), and in evolving interactions between CSCs and extracellular matrix. Among other aspects, we analyze the role and changes of expression of key adhesion molecules as cancer progresses and metastases develop. Here, the role of cadherins, integrins, as well as selected transcription factors like Twist and Snail is highlighted, not only in the regulation of epithelial-to-mesenchymal transition but also in the avoidance of anoikis. Finally, we briefly discuss recent developments and new strategies targeting CSCs, which focus on adhesion molecules or targeting tumor vasculature.
PDF
