Amniotic fluid-derived stem cells: potential factories of natural and mimetic strategies for congenital malformations.

Background: Mesenchymal stem cells (MSCs) from gestational tissues represent promising strategies for in utero treatment of congenital malformations, but plasticity and required high-risk surgical procedures limit their use. Here we propose natural exosomes (EXOs) isolated from amniotic fluid-MSCs (AF-MSCs), and their mimetic counterparts (MIMs), as valid, stable, and minimally invasive therapeutic alternatives. Methods: MIMs were generated from AF-MSCs by combining sequential filtration steps through filter membranes with different porosity and size exclusion chromatography columns. Physiochemical and molecular characterization was performed to compare them to EXOs released from the same number of cells. The possibility to exploit both formulations as mRNA-therapeutics was explored by evaluating cell uptake (using two different cell types, fibroblasts, and macrophages) and mRNA functionality overtime in an in vitro experimental setting as well as in an ex vivo, whole embryo culture using pregnant C57BL6 dams. Results: Molecular and physiochemical characterization showed no differences between EXOs and MIMs, with MIMs determining a 3-fold greater yield. MIMs delivered a more intense and prolonged expression of mRNA encoding for green fluorescent protein (GFP) in macrophages and fibroblasts. An ex-vivo whole embryo culture demonstrated that MIMs mainly accumulate at the level of the yolk sac, while EXOs reach the embryo. Conclusions: The present data confirms the potential application of EXOs for the prenatal repair of neural tube defects and proposes MIMs as prospective vehicles to prevent congenital malformations caused by in utero exposure to drugs.

Transcriptomic analysis reveals the anti-cancer effect of gestational mesenchymal stem cell secretome.

The environment created during embryogenesis contributes to reducing aberrations that drive structural malformations and tumorigenesis. In this study, we investigate the anti-cancer effect of mesenchymal stem cells (MSCs) derived from 2 different gestational tissues, the amniotic fluid (AF) and the chorionic villi (CV), with emphasis on their secretome. Transcriptomic analysis was performed on patient-derived AF- and CV-MSCs collected during prenatal diagnosis and identified both mRNAs and lncRNAs, involved in tissue homeostasis and inhibiting biological processes associated with the etiology of aggressive cancers while regulating immune pathways shown to be important in chronic disorders. Secretome enrichment analysis also identified soluble moieties involved in target cell regulation, tissue homeostasis, and cancer cell inhibition through the highlighted Wnt, TNF, and TGF-ß signaling pathways. Transcriptomic data were experimentally confirmed through in vitro assays, by evaluating the anti-cancer effect of the media conditioned by AF- and CV-MSCs and the exosomes derived from them on ovarian cancer cells, revealing inhibitory effects in 2D (by reducing cell viability and inducing apoptosis) and in 3D conditions (by negatively interfering with spheroid formation). These data provide molecular insights into the potential role of gestational tissues-derived MSCs as source of anti-cancer factors, paving the way for the development of therapeutics to create a pro-regenerative environment for tissue restoration following injury, disease, or against degenerative disorders.

Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome.

BACKGROUND: Down syndrome (DS) clinical multisystem condition is generally considered the result of a genetic imbalance generated by the extra copy of chromosome 21. Recent discoveries, however, demonstrate that the molecular mechanisms activated in DS compared to euploid individuals are more complex than previously thought. Here, we utilize mesenchymal stem cells from chorionic villi (CV) to uncover the role of comprehensive functional genomics-based understanding of DS complexity. METHODS: Next-generation sequencing coupled with bioinformatic analysis was performed on CV obtained from women carrying fetuses with DS (DS-CV) to reveal specific genome-wide transcriptional changes compared to their euploid counterparts. Functional assays were carried out to confirm the biological processes identified as enriched in DS-CV compared to CV (i.e., cell cycle, proliferation features, immunosuppression and ROS production). RESULTS: Genes located on chromosomes other than the canonical 21 (Ch. 2, 6 and 22) are responsible for the impairment of life-essential pathways, including cell cycle regulation, innate immune response and reaction to external stimuli were found to be differentially expressed in DS-CV. Experimental validation confirmed the key role of the biological pathways regulated by those genes in the etiology of such a multisystem condition. CONCLUSIONS: NGS dataset generated in this study highlights the compromised functionality in the proliferative rate and in the innate response of DS-associated clinical conditions and identifies DS-CV as suitable tools for the development of specifically tailored, personalized intervention modalities.

Editorial: Precision Medicine in Obstetrics: Pregnancy Complication.

Millions of women give birth every year worldwide [...].

Nanotechnologies in Obstetrics and Cancer during Pregnancy: A Narrative Review.

Nanotechnology, the art of engineering structures on a molecular level, offers the opportunity to implement new strategies for the diagnosis and management of pregnancy-related disorders. This review aims to summarize the current state of nanotechnology in obstetrics and cancer in pregnancy, focusing on existing and potential applications, and provides insights on safety and future directions. A systematic and comprehensive literature assessment was performed, querying the following databases: PubMed/Medline, Scopus, and Endbase. The databases were searched from their inception to 22 March 2022. Five independent reviewers screened the items and extracted those which were more pertinent within the scope of this review. Although nanotechnology has been on the bench for many years, most of the studies in obstetrics are preclinical. Ongoing research spans from the development of diagnostic tools, including optimized strategies to selectively confine contrast agents in the maternal bloodstream and approaches to improve diagnostics tests to be used in obstetrics, to the synthesis of innovative delivery nanosystems for therapeutic interventions. Using nanotechnology to achieve spatial and temporal control over the delivery of therapeutic agents (e.g., commonly used drugs, more recently defined formulations, or gene therapy-based approaches) offers significant advantages, including the possibility to target specific cells/tissues of interest (e.g., the maternal bloodstream, uterus wall, or fetal compartment). This characteristic of nanotechnology-driven therapy reduces side effects and the amount of therapeutic agent used. However, nanotoxicology appears to be a significant obstacle to adopting these technologies in clinical therapeutic praxis. Further research is needed in order to improve these techniques, as they have tremendous potential to improve the accuracy of the tests applied in clinical praxis. This review showed the increasing interest in nanotechnology applications in obstetrics disorders and pregnancy-related pathologies to improve the diagnostic algorithms, monitor pregnancy-related diseases, and implement new treatment strategies.

Early prediction of clinical response to checkpoint inhibitor therapy in human solid tumors through mathematical modeling.

Background: Checkpoint inhibitor therapy of cancer has led to markedly improved survival of a subset of patients in multiple solid malignant tumor types, yet the factors driving these clinical responses or lack thereof are not known. We have developed a mechanistic mathematical model for better understanding these factors and their relations in order to predict treatment outcome and optimize personal treatment strategies. Methods: Here, we present a translational mathematical model dependent on three key parameters for describing efficacy of checkpoint inhibitors in human cancer: tumor growth rate (α), tumor-immune infiltration (Λ), and immunotherapy-mediated amplification of anti-tumor response (µ). The model was calibrated by fitting it to a compiled clinical tumor response dataset (n = 189 patients) obtained from published anti-PD-1 and anti-PD-L1 clinical trials, and then validated on an additional validation cohort (n = 64 patients) obtained from our in-house clinical trials. Results: The derived parameters Λ and µ were both significantly different between responding versus nonresponding patients. Of note, our model appropriately classified response in 81.4% of patients by using only tumor volume measurements and within 2 months of treatment initiation in a retrospective analysis. The model reliably predicted clinical response to the PD-1/PD-L1 class of checkpoint inhibitors across multiple solid malignant tumor types. Comparison of model parameters to immunohistochemical measurement of PD-L1 and CD8+ T cells confirmed robust relationships between model parameters and their underlying biology. Conclusions: These results have demonstrated reliable methods to inform model parameters directly from biopsy samples, which are conveniently obtainable as early as the start of treatment. Together, these suggest that the model parameters may serve as early and robust biomarkers of the efficacy of checkpoint inhibitor therapy on an individualized per-patient basis. Funding: We gratefully acknowledge support from the Andrew Sabin Family Fellowship, Center for Radiation Oncology Research, Sheikh Ahmed Center for Pancreatic Cancer Research, GE Healthcare, Philips Healthcare, and institutional funds from the University of Texas M.D. Anderson Cancer Center. We have also received Cancer Center Support Grants from the National Cancer Institute (P30CA016672 to the University of Texas M.D. Anderson Cancer Center and P30CA072720 the Rutgers Cancer Institute of New Jersey). This research has also been supported in part by grants from the National Science Foundation Grant DMS-1930583 (ZW, VC), the National Institutes of Health (NIH) 1R01CA253865 (ZW, VC), 1U01CA196403 (ZW, VC), 1U01CA213759 (ZW, VC), 1R01CA226537 (ZW, RP, WA, VC), 1R01CA222007 (ZW, VC), U54CA210181 (ZW, VC), and the University of Texas System STARS Award (VC). BC acknowledges support through the SER Cymru II Programme, funded by the European Commission through the Horizon 2020 Marie Sklodowska-Curie Actions (MSCA) COFUND scheme and the Welsh European Funding Office (WEFO) under the European Regional Development Fund (ERDF). EK has also received support from the Project Purple, NIH (U54CA210181, U01CA200468, and U01CA196403), and the Pancreatic Cancer Action Network (16-65-SING). MF was supported through NIH/NCI center grant U54CA210181, R01CA222959, DoD Breast Cancer Research Breakthrough Level IV Award W81XWH-17-1-0389, and the Ernest Cockrell Jr. Presidential Distinguished Chair at Houston Methodist Research Institute. RP and WA received serial research awards from AngelWorks, the Gillson-Longenbaugh Foundation, and the Marcus Foundation. This work was also supported in part by grants from the National Cancer Institute to SHC (R01CA109322, R01CA127483, R01CA208703, and U54CA210181 CITO pilot grant) and to PYP (R01CA140243, R01CA188610, and U54CA210181 CITO pilot grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

TFEB, SIRT1, CARM1, Beclin-1 expression and PITX2 methylation in breast cancer chemoresistance: a retrospective study.

BACKGROUND: Breast cancer chemoresistance is attributed to a wide variety of mechanisms, including autophagy. Transcription factor EB (TFEB) has been recently identified and characterized as one major regulator of autophagy and lysosomal genesis. OBJECTIVE: This study aims to evaluate the prognostic impact of TFEB and its pathway in breast cancer chemoresistance. METHODS: This retrospective study analyzes the expression of TFEB, CARM1, SIRT1, and Beclin-1 and the methylation of PITX2 in breast carcinoma. A group of breast cancer patients treated with chemotherapy, who relapsed within 12 months from treatment initiation, were compared to a sub-cohort of chemo-treated patients who did not recur within 12 months of follow-up. The expression of TFEB, CARM1, SIRT1, and Belcin-1 was analyzed using immunohistochemistry or RT-PCR on formalin-fixed paraffin-embedded samples. PITX2 methylation was tested with the diagnostic CE-marked kit Therascreen PITX2 RGQ PCR. In the final model, 136 cases of chemo-treated breast cancer were included. RESULTS: A higher TFEB and Beclin-1 expression correlate with shorter survival in patients with chemo-treated invasive breast cancer (respectively HR 3.46, CI.95 1.27-9.47, p < 0.05 and 7.11, CI.95 2.54-19.9). TFEB, CARM1, and SIRT1 are positively correlated with Beclin-1. The protein expression of SIRT1 is significantly associated with TFEB and CARM1 so that a very low SIRT1 expression (lower than the first quartile of the H-score distribution) correlates with a low expression of TFEB and CARM1 and with longer survival. SIRT1 seems to have a lower H-score in the basal-like and HER2-enriched tumors than the luminal subtypes. Beclin-1 and TFEB seem to have a higher H-score in the basal-like and HER2-enriched tumors than the luminal subtypes. PITX2 methylation analysis was feasible only in 65% of the selected samples, but no significant differences between cases and controls were found, and there was also no correlation with the expression of the TFEB pathway. CONCLUSIONS: TFEB, SIRT1, and Beclin-1 seem to have a potential prognostic significance in patients with chemo-treated breast cancer, likely because of their role in the regulation of autophagy. In addition, no correlation between TFEB and PITX2 methylation was found, likely because they perform two different roles within the autophagy process.

Assessment of the immune landscapes of advanced ovarian cancer in an optimized in vivo model.

BACKGROUND: Ovarian cancer (OC) is typically diagnosed late, associated with high rates of metastasis and the onset of ascites during late stage disease. Understanding the tumor microenvironment and how it impacts the efficacy of current treatments, including immunotherapies, needs effective in vivo models that are fully characterized. In particular, understanding the role of immune cells within the tumor and ascitic fluid could provide important insights into why OC fails to respond to immunotherapies. In this work, we comprehensively described the immune cell infiltrates in tumor nodules and the ascitic fluid within an optimized preclinical model of advanced ovarian cancer. METHODS: Green Fluorescent Protein (GFP)-ID8 OC cells were injected intraperitoneally into C57BL/6 mice and the development of advanced stage OC monitored. Nine weeks after tumor injection, mice were sacrificed and tumor nodules analyzed to identify specific immune infiltrates by immunohistochemistry. Ascites, developed in tumor bearing mice over a 10-week period, was characterized by mass cytometry (CyTOF) to qualitatively and quantitatively assess the distribution of the immune cell subsets, and their relationship to ascites from ovarian cancer patients. RESULTS: Tumor nodules in the peritoneal cavity proved to be enriched in T cells, antigen presenting cells and macrophages, demonstrating an active immune environment and cell-mediated immunity. Assessment of the immune landscape in the ascites showed the predominance of CD8+ , CD4+ , B- , and memory T cells, among others, and the coexistance of different immune cell types within the same tumor microenvironment. CONCLUSIONS: We performed, for the first time, a multiparametric analysis of the ascitic fluid and specifically identify immune cell populations in the peritoneal cavity of mice with advanced OC. Data obtained highlights the impact of CytOF as a diagnostic tool for this malignancy, with the opportunity to concomitantly identify novel targets, and define personalized therapeutic options.

Biomimetic immunomodulation strategies for effective tissue repair and restoration.

Inflammation plays a central role in wound healing following injury or disease and is mediated by a precise cascade of cellular and molecular events. Unresolved inflammatory processes lead to chronic inflammation and fibrosis, which can result in prolonged wound healing lasting months or years that hampers tissue function. Therapeutic interventions mediated by immunomodulatory drugs, cells, or biomaterials, are therefore most effective during the inflammatory phase of wound healing when a pro-regenerative environment is essential. In this review, we discuss the advantages of exploiting knowledge of the native tissue microenvironment to develop therapeutics capable of modulating the immune response and promoting functional tissue repair. In particular, we provide examples of the most recent biomimetic platforms proposed to accomplish this goal, with an emphasis on those able to induce macrophage polarization towards a pro-regenerative phenotype.

Amphibian regeneration and mammalian cancer: Similarities and contrasts from an evolutionary biology perspective: Comparing the regenerative potential of mammalian embryos and urodeles to develop effective strategies against human cancer.

Here we review and discuss the link between regeneration capacity and tumor suppression comparing mammals (embryos versus adults) with highly regenerative vertebrates. Similar to mammal embryo morphogenesis, in amphibians (essentially newts and salamanders) the reparative process relies on a precise molecular and cellular machinery capable of sensing abnormal signals and actively reprograming or eliminating them. As the embryo's evil twin, tumor also retains common functional attributes. The immune system plays a pivotal role in maintaining a physiological balance to provide surveillance against tumor initiation or to support its initiation and progression. We speculate that susceptibility to cancer development in adult mammals may be determined by the loss of an advanced regenerative capability during evolution and believe that gaining mechanistic insights into how regenerative capacity linked to tumor suppression is postnatally lost in mammals might illuminate an as yet unrecognized route to cancer treatment.

Biomimetic and immunomodulatory therapeutics as an alternative to natural exosomes for vascular and cardiac applications.

Inflammation is a central mechanism in cardiovascular diseases (CVD), where sustained oxidative stress and immune responses contribute to cardiac remodeling and impairment. Exosomes are extracellular vesicles released by cells to communicate with their surroundings and to modulate the tissue microenvironment. Recent evidence indicates their potential as cell-free immunomodulatory therapeutics for CVD, preventing cell death and fibrosis while inducing wound healing and angiogenesis. Biomimetic exosomes are semi-synthetic particles engineered using essential moieties present in natural exosomes (lipids, RNA, proteins) to reproduce their therapeutic effects while improving on scalability and standardization due to the ample range of moieties available to produce them. In this review, we provide an up-to-date description of the use of exosomes for CVD and offer our vision on the areas of opportunity for the development of biomimetic strategies. We also discuss the current limitations to overcome in the process towards their translation into clinic.

Immune (Cell) Derived Exosome Mimetics (IDEM) as a Treatment for Ovarian Cancer.

Exosomes are physiologically secreted nanoparticles recently established as natural delivery systems involved in cell-to-cell communication and content exchange. Due to their inherent targeting potential, exosomes are currently being harnessed for the development of anti-cancer therapeutics. Clinical trials evaluating their effectiveness are demonstrating safety and promising outcomes. However, challenging large-scale production, isolation, modification and purification of exosomes are current limitations for the use of naturally occurring exosomes in the clinic. Exosome mimetics hold the promise to improve the delivery of bioactive molecules with therapeutic efficacy, while achieving scalability and increasing bioavailability. In this study, we propose the development of Immune Derived Exosome Mimetics (IDEM) as a scalable approach to target and defeat ovarian cancer cells. IDEM were fabricated from monocytic cells by combining sequential filtration steps through filter membranes with different porosity and size exclusion chromatography columns. The physiochemical and molecular characteristics of IDEM were compared to those of natural exosomes (EXO). Nanoparticle Tracking Analysis confirmed a 2.48-fold increase in the IDEM production yields compared to EXO, with similar exosomal markers profiles (CD81, CD63) as demonstrated by flow cytometry and ELISA. To exploit the prospective of IDEM to deliver chemotherapeutics, doxorubicin (DOXO) was used as a model drug. IDEM showed higher encapsulation efficiency and drug release over time compared to EXO. The uptake of both formulations by SKOV-3 ovarian cancer cells was assessed by confocal microscopy and flow cytometry, showing an incremental drug uptake over time. The analysis of the cytotoxic and apoptotic effect of DOXO-loaded nanoparticles both in 2D and 3D culture systems proved IDEM as a more efficient system as compared to free DOXO, unraveling the advantage of IDEM in reducing side-effects while increasing cytotoxicity of targeted cells, by delivering smaller amount of the chemotherapeutic agent. The high yields of IDEM obtained compared to natural exosomes together with the time-effectiveness and reproducibility of their production method make this approach potentially exploitable for clinical applications. Most importantly, the appreciable cytotoxic effect observed on ovarian cancer in vitro systems sets the ground for the development of compelling nanotherapeutic candidates for the treatment of this malady and will be further evaluated.

Enhanced In Vivo Vascularization of 3D-Printed Cell Encapsulation Device Using Platelet-Rich Plasma and Mesenchymal Stem Cells.

The current standard for cell encapsulation platforms is enveloping cells in semipermeable membranes that physically isolate transplanted cells from the host while allowing for oxygen and nutrient diffusion. However, long-term viability and function of encapsulated cells are compromised by insufficient oxygen and nutrient supply to the graft. To address this need, a strategy to achieve enhanced vascularization of a 3D-printed, polymeric cell encapsulation platform using platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs) is investigated. The study is conducted in rats and, for clinical translation relevance, in nonhuman primates (NHP). Devices filled with PRP, MSCs, or vehicle hydrogel are subcutaneously implanted in rats and NHP and the amount and maturity of penetrating blood vessels assessed via histopathological analysis. In rats, MSCs drive the strongest angiogenic response at early time points, with the highest vessel density and endothelial nitric oxide synthase (eNOS) expression. In NHP, PRP and MSCs result in similar vessel densities but incorporation of PRP ensues higher levels of eNOS expression. Overall, enrichment with PRP and MSCs yields extensive, mature vascularization of subcutaneous cell encapsulation devices. It is postulated that the individual properties of PRP and MSCs can be leveraged in a synergistic approach for maximal vascularization of cell encapsulation platforms.

Neovascularized implantable cell homing encapsulation platform with tunable local immunosuppressant delivery for allogeneic cell transplantation.

Cell encapsulation is an attractive transplantation strategy to treat endocrine disorders. Transplanted cells offer a dynamic and stimulus-responsive system that secretes therapeutics based on patient need. Despite significant advancements, a challenge in allogeneic cell encapsulation is maintaining sufficient oxygen and nutrient exchange, while providing protection from the host immune system. To this end, we developed a subcutaneously implantable dual-reservoir encapsulation system integrating in situ prevascularization and local immunosuppressant delivery, termed NICHE. NICHE structure is 3D-printed in biocompatible polyamide 2200 and comprises of independent cell and drug reservoirs separated by a nanoporous membrane for sustained local release of immunosuppressant. Here we present the development and characterization of NICHE, as well as efficacy validation for allogeneic cell transplantation in an immunocompetent rat model. We established biocompatibility and mechanical stability of NICHE. Further, NICHE vascularization was achieved with the aid of mesenchymal stem cells. Our study demonstrated sustained local elution of immunosuppressant (CTLA4Ig) into the cell reservoir protected transcutaneously-transplanted allogeneic Leydig cells from host immune destruction during a 31-day study, and reduced systemic drug exposure by 12-fold. In summary, NICHE is the first encapsulation platform achieving both in situ vascularization and immunosuppressant delivery, presenting a viable strategy for allogeneic cell transplantation.

Immunotherapeutic Transport Oncophysics: Space, Time, and Immune Activation in Cancer.

Immuno-oncology has gained momentum thanks to the success of strategies aimed at enhancing immune-mediated antitumor response. The field of immunotherapeutic transport oncophysics investigates the physical processes that drive cancer immunotherapies. This review discusses three main aspects that determine the outcome of an immunotherapy-based treatment from a physical point of view; (i) space, the distribution of cancer and immune cells within tumor masses, (ii) time, the temporal dynamic of immune response against tumors, and (iii) activity, the ability of immune cell populations to suppress cancer. Upon introducing these topics with examples from the literature, we investigate in detail two cases where the interplay between space, time, and activation variables determines immune response: nanodendritic cell vaccines and immunosuppression in ovarian cancer.

Bioactive Immunomodulatory Compounds: A Novel Combinatorial Strategy for Integrated Medicine in Oncology? BAIC Exposure in Cancer Cells.

The Standardized Cultured Extract of Lentinula edodes Mycelia (also known as Active Hexose Correlated Compound, AHCC) and Wasabia japonica (Wasabi) are natural nutritional supplements known for their immunomodulatory and anticancer potential. The aim of this study was to evaluate the combinatorial effect of the bioactive immunomodulatory compound (BAIC), obtained by combining Wasabi and AHCC, on human breast (MCF-7) and pancreatic (Panc02) adenocarcinoma cell lines. Data obtained revealed that BAIC determines a striking decline in cancer cell growth at minimal concentrations compared with the use of Wasabi and AHCC as single agents. A significant increase in the G0/G1 subpopulation together with a marked augmentation in the percentage of apoptotic cells was demonstrated by flow cytometry, together with a significant upregulation in the expression of genes associated to the apoptotic cascade in both cell lines. The inhibitory role BAIC plays in mammospheres formation from MCF-7-derived cancer stem cells was shown with a marked reduction in size and number. Interestingly, when BAIC was exposed to monocytic cells, no cytotoxic effects were observed. A monocytes-to-macrophages differentiation was rather observed with the concomitant acquisition of an anti-inflammatory phenotype. Taken together, our findings suggest that BAIC could be used as a potential integration of standard chemotherapy treatments because of the improved inhibitory activity on cancer cell proliferation and reduced potential adverse effects.

Nanotechnology and Immunotherapy in Ovarian Cancer: Tracing New Landscapes.

Ovarian cancer (OC) is the seventh most common cancer in women worldwide. Standard therapeutic treatments involve debulking surgery combined with platinum-based chemotherapies. Of the patients with advanced-stage cancer who initially respond to current treatments, 50%-75% relapse. Immunotherapy-based approaches aimed at boosting antitumor immunity have recently emerged as promising tools to challenge tumor progression. Treatments with inhibitors of immune checkpoint molecules have shown impressive results in other types of tumors. However, only 15% of checkpoint inhibitors evaluated have proven successful in OC due to the immunosuppressive environment of the tumor and the transport barriers. This limits the efficacy of the existing immunotherapies. Nanotechnology-based delivery systems hold the potential to overcome such limitations. Various nanoformulations including polymeric, liposomes, and lipid-polymer hybrid nanoparticles have already been proposed to improve the biodistribution and targeting capabilities of drugs against tumor-associated immune cells, including dendritic cells and macrophages. In this review, we examine the impact of immunotherapeutic approaches that are currently under consideration for the treatment of OC. In this review, we also provide a comprehensive analysis of the existing nanoparticle-based synthetic strategies and their limitations and advantages over standard treatments. Furthermore, we discuss how the strength of the combination of nanotechnology with immunotherapy may help to overcome the current therapeutic limitations associated with their individual application and unravel a new paradigm in the treatment of this malignancy.

Immune tuning scaffold for the local induction of a pro-regenerative environment.

In mammals, tissue regeneration is accomplished through a well-regulated, complex cascade of events. The disruption of the cellular and molecular processes involved in tissue healing might lead to scar formation. Most tissue engineering approaches have tried to improve the regenerative outcome following an injury, through the combination of biocompatible materials, stem cells and bioactive factors. However, implanted materials can cause further healing impairments due to the persistent inflammatory stimuli that trigger the onset of chronic inflammation. Here, it is described at the molecular, cellular and tissue level, the body response to a functionalized biomimetic collagen scaffold. The grafting of chondroitin sulfate on the surface of the scaffold is able to induce a pro-regenerative environment at the site of a subcutaneous implant. The early in situ recruitment, and sustained local retention of anti-inflammatory macrophages significantly reduced the pro-inflammatory environment and triggered a different healing cascade, ultimately leading to collagen fibril re-organization, blood vessel formation, and scaffold integration with the surrounding native tissue.

Heparan Sulfate: A Potential Candidate for the Development of Biomimetic Immunomodulatory Membranes.

Clinical trials have demonstrated that heparan sulfate (HS) could be used as a therapeutic agent for the treatment of inflammatory diseases. Its anti-inflammatory effect makes it suitable for the development of biomimetic innovative strategies aiming at modulating stem cells behavior toward a pro-regenerative phenotype in case of injury or inflammation. Here, we propose collagen type I meshes fabricated by solvent casting and further crosslinked with HS (HS-Col) to create a biomimetic environment resembling the extracellular matrix of soft tissue. HS-Col meshes were tested for their capability to provide physical support to stem cells' growth, maintain their phenotypes and immunosuppressive potential following inflammation. HS-Col effect on stem cells was investigated in standard conditions as well as in an inflammatory environment recapitulated in vitro through a mix of pro-inflammatory cytokines (tumor necrosis factor-α and interferon-gamma; 20 ng/ml). A significant increase in the production of molecules associated with immunosuppression was demonstrated in response to the material and when cells were grown in presence of pro-inflammatory stimuli, compared to bare collagen membranes (Col), leading to a greater inhibitory potential when mesenchymal stem cells were exposed to stimulated peripheral blood mononuclear cells. Our data suggest that the presence of HS is able to activate the molecular machinery responsible for the release of anti-inflammatory cytokines, potentially leading to a faster resolution of inflammation.