Abstract Exosomes can selectively secrete harmful metabolic substances from cells to maintain cellular homeostasis, and complex crosstalk occurs between exosomes and tumor-associated macrophages (TAMs) in the glioma immune microenvironment. However, the precise mechanisms by which these exosome-encapsulated cargos create an immunosuppressive microenvironment remain unclear. Herein, we investigated the effect of glioma-derived exosomes (GDEs) on macrophage polarization and glioma progression. We performed sequencing analysis of cerebrospinal fluid (CSF) and tumor tissues from glioma patients to identify functional microRNAs (miRNAs). High levels of miR-3591-3p were found in CSF and GDEs but not in normal brain tissue or glial cells. Functionally, GDEs and miR-3591-3p significantly induced M2 macrophage polarization and increased the secretion of IL10 and TGFβ1, which in turn promoted glioma invasion and migration. Moreover, miR-3591-3p overexpression in glioma cell lines resulted in G2/M arrest and markedly increased apoptosis. Mechanistically, miR-3591-3p can directly target CBLB and MAPK1 in macrophages and glioma cells, respectively, and further activate the JAK2/PI3K/AKT/mTOR, JAK2/STAT3, and MAPK signaling pathways. In vivo experiments confirmed that macrophages lentivirally transduced with miR-3591-3p can significantly promote glioma progression. Thus, our study demonstrates that tumor-suppressive miR-3591-3p in glioma cells can be secreted via exosomes and target TAMs to induce the formation of an immunosuppressive microenvironment. Collectively, these findings provide new insights into the role of glioma exosomal miRNAs in mediating the establishment of an immunosuppressive tumor microenvironment and show that miR-3591-3p may be a valuable biomarker and that blocking the encapsulation of miR-3591-3p into exosomes may become a novel immunotherapeutic strategy for glioma. 

https://www.nature.com/articles/s41388-022-02457-w.pdf

Tumor-derived exosomes deliver the tumor suppressor miR-3591-3p to induce M2 macrophage polarization and promote glioma progression

Quantitative systems pharmacology (QSP) is a quantitative and mechanistic platform describing the phenotypic interaction between drugs, biological networks, and disease conditions to predict optimal therapeutic response. In this meta-analysis study, we review the utility of the QSP platform in drug development and therapeutic strategies based on recent publications (2019-2021). We gathered recent original QSP models and described the diversity of their applications based on therapeutic areas, methodologies, software platforms, and functionalities. The collection and investigation of these publications can assist in providing a repository of recent QSP studies to facilitate the discovery and further reusability of QSP models. Our review shows that the largest number of QSP efforts in recent years is in Immuno-Oncology. We also addressed the benefits of integrative approaches in this field by presenting the applications of Machine Learning methods for drug discovery and QSP models. Based on this meta-analysis, we discuss the advantages and limitations of QSP models and propose fields where the QSP approach constitutes a valuable interface for more investigations to tackle complex diseases and improve drug development.

Recent applications of quantitative systems pharmacology and machine learning models across diseases

Background Anti-GD2 monoclonal antibody immunotherapy has significantly improved the overall survival rate for high-risk neuroblastoma patients. However, 40% of patients fail to respond or develop resistance to treatment, and the molecular mechanisms by which this occurs remain poorly understood. Tumor-derived small extracellular vesicles (sEVs) have emerged as critical regulators in modulating the response to immunotherapy. In this study, we investigated the role of neuroblastoma-derived sEVs in promoting resistance to the anti-GD2 monoclonal antibody dinutuximab. Moreover, to determine whether pharmacologic inhibition of sEV secretion sensitizes tumors to dinutuximab treatment, we combined dinutuximab with tipifarnib, a farnesyltransferase inhibitor that inhibits sEV secretion. Methods We investigated the role of neuroblastoma-derived sEVs in modulating the response to dinutuximab by utilizing the syngeneic 9464D-GD2 mouse model. The effect of neuroblastoma-derived sEVs in modulating the tumor microenvironment (TME) and host immune system were evaluated by RNA-sequencing and flow cytometry. Importantly, we used this mouse model to investigate the efficacy of tipifarnib in sensitizing neuroblastoma tumors to dinutuximab. The effect of tipifarnib on both the TME and host immune system were assessed by flow cytometry. Results We demonstrated that neuroblastoma-derived sEVs significantly attenuated the efficacy of dinutuximab in vivo and modulated tumor immune cell infiltration upon dinutuximab treatment to create an immunosuppressive TME that contains more tumor-associated macrophages and fewer tumor-infiltrating NK cells. In addition, we demonstrated that neuroblastoma-derived sEVs suppress splenic NK cell maturation in vivo and dinutuximab-induced NK cell-mediated antibody-dependent cellular cytotoxicity in vitro. Importantly, tipifarnib drastically enhanced the efficacy of dinutuximab-mediated inhibition of tumor growth and prevented the immunosuppressive effects of neuroblastoma-derived sEVs in vivo. Conclusions These preclinical findings uncover a novel mechanism by which neuroblastoma-derived sEVs modulate the immune system to promote resistance to dinutuximab and suggest that tipifarnib-mediated inhibition of sEV secretion may serve as a viable treatment strategy to enhance the antitumor efficacy of anti-GD2 immunotherapy in high-risk neuroblastoma patients.

/pdf/small-extracellular-vesicles-induce-resistance-to-anti-gd2-1hiuntm0.pdf

Small extracellular vesicles induce resistance to anti-GD2 immunotherapy unveiling tipifarnib as an adjunct to neuroblastoma immunotherapy

Simple Summary In this review, we present current knowledge of sex hormones in the process of development of malignant diseases. The impact of sex hormones on immune system is presented. A special account is devoted to estrogens and their role in modification of anticancer immune response. Abstract Sex hormones are included in many physiological and pathological pathways. Estrogens belong to steroid hormones active in female sex. Estradiol (E2) is the strongest female sex hormone and, with its receptors, contributes to oncogenesis, cancer progression and response to treatment. In recent years, a role of immunosurveillance and suppression of immune response in malignancy has been well defined, forming the basis for cancer immunotherapy. The interplay of sex hormones with cancer immunity, as well as the response to immune checkpoint inhibitors, is of interest. In this review, we investigate the impact of sex hormones on natural immune response with respect to main active elements in anticancer immune surveillance: dendritic cells, macrophages, lymphocytes and checkpoint molecules. We describe the main sex-dependent tumors and the contribution of estrogen in their progression, response to treatment and especially modulation of anticancer immune response.

/pdf/estrogens-cancer-and-immunity-1itowkf7.pdf

Estrogens, Cancer and Immunity

There is a complete lack of highly sensitive and specific biomarkers for early pancreatic ductal adenocarcinoma (PDAC) diagnosis, limiting multi-modal therapeutic options. Mitochondrial DNA (mtDNA) is an excellent resource for biomarker discovery because of its high copy number and increased mutational frequency in cancer cells. We examined if mtDNA mutations can be detected in circulating extracellular vesicles (EVs) of PDAC patients and used for discerning between cancer and non-cancer subjects. A greater yield of circulating EVs (~ 1.4 fold; p = 0.002) was obtained in PDAC patients (n = 20) than non-cancer (NC) individuals (n = 10). PDAC-EVs contained a higher quantity of total DNA (~ 5.5 folds; p = 0.0001) than NC-EVs and had greater enrichment of mtDNA (~ 14.02-fold; p = 0.0001). PDAC-EVs also had higher levels of cardiolipin (a mitochondrial inner-membrane phospholipid), suggestive of their mitochondrial origin. All mtDNA mutations in PDAC-EVs were unique and frequency was remarkably higher. Most mtDNA mutations (41.5%) in PDAC-EVs were in the respiratory complex-I (RCI) (ND1-ND6), followed by the RCIII gene (CYTB; 11.2%). Among the non-coding genes, D-Loop and RNR2 exhibited the most mutations (15.2% each). Altogether, our study establishes, for the first time, that mtDNA mutations can be detected in circulating EVs and potentially serve as a tool for reliable PDAC diagnosis. 

/pdf/detection-of-mitochondrial-dna-mutations-in-circulating-83ol01ay.pdf

Detection of mitochondrial DNA mutations in circulating mitochondria-originated extracellular vesicles for potential diagnostic applications in pancreatic adenocarcinoma

Immunotherapeutic drugs including immune checkpoint blockade antibodies have been approved to treat patients in many types of cancers. However, some patients have little or no reaction to the immunotherapy drugs. The mechanisms underlying resistance to tumor immunotherapy are complicated and involve multiple aspects, including tumor-intrinsic factors, formation of immunosuppressive microenvironment, and alteration of tumor and stromal cell metabolism in the tumor microenvironment. T cell is critical and participates in every aspect of antitumor response, and T cell dysfunction is a severe barrier for effective immunotherapy for cancer. Emerging evidence indicates that extracellular vesicles (EVs) secreted by tumor is one of the major factors that can induce T cell dysfunction. Tumor-derived EVs are widely distributed in serum, tissues, and the tumor microenvironment of patients with cancer, which serve as important communication vehicles for cancer cells. In addition, tumor-derived EVs can carry a variety of immune suppressive signals driving T cell dysfunction for tumor immunity. In this review, we explore the potential mechanisms employed by tumor-derived EVs to control T cell development and effector function within the tumor microenvironment. Especially, we focus on current understanding of how tumor-derived EVs molecularly and metabolically reprogram T cell fates and functions for tumor immunity. In addition, we discuss potential translations of targeting tumor-derived EVs to reconstitute suppressive tumor microenvironment or to develop antigen-based vaccines and drug delivery systems for cancer immunotherapy.

https://jitc.bmj.com/content/jitc/9/10/e003217.full.pdf

Emerging role of tumor-derived extracellular vesicles in T cell suppression and dysfunction in the tumor microenvironment.

Phosphorylation of the Gα protein Gpa2 promotes protein kinase A signaling in yeast.

The Ycx1 protein encoded by the yeast YDL206W gene plays a role in calcium and calcineurin signaling

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Emerging role of tumor-derived extracellular vesicles in T cell suppression and dysfunction in the tumor microenvironment.

Phosphorylation of the Gα protein Gpa2 promotes protein kinase A signaling in yeast.

The Ycx1 protein encoded by the yeast YDL206W gene plays a role in calcium and calcineurin signaling