Despite the skepticism that once prevailed among immunologists, it is now widely accepted that the normal immune system harbors a T-cell population, called regulatory T cells (Treg cells), specialized for immune suppression. It was first shown that depletion of a T-cell subpopulation from normal rodents produced autoimmune disease. Search for a molecular marker specific for such autoimmune-preventive Treg cells has revealed that the majority, if not all, of them constitutively express the CD25 molecule as depletion of CD25+CD4+ T cells spontaneously evokes autoimmune disease in otherwise normal rodents. The expression of CD25 by Treg cells has made it possible to delineate their developmental pathways, in particular their thymic development, and establish simple in vitro assay for assessing their suppressive activity. The marker and the in vitro assay have helped to identify human Treg cells with similar functional and phenotypic characteristics. Recent efforts have shown that natural Treg cells specifically express the transcription factor Foxp3 and that mutations of the Foxp3 gene produce a variety of immunological diseases in humans and rodents. Specific expression of Foxp3 in natural Treg cells has enabled their functional and developmental characterization by genetic approach. These studies altogether have provided firm evidence for Foxp3+CD25+CD4+ Treg cells as an indispensable cellular constituent of the normal immune system for establishing and maintaining immunologic self-tolerance and immune homeostasis. Treg cells are now within the scope of clinical use to treat immunological diseases and control physiological and pathological immune responses.

Regulatory T Cells

Hypoxia-inducible factor 1 (HIF-1) plays an indispensable role in the hypoxic tumor microenvironment. Hypoxia and HIF-1 are involved in multiple aspects of tumor progression, such as metastasis, angiogenesis, and immune evasion. In innate and adaptive immune systems, malignant tumor cells avoid their recognition and destruction by HIF-1. Tumor immune evasion allows cancer cells to proliferate and metastasize and is associated with immunotherapy failure and chemoresistance. In the hypoxic tumor microenvironment, HIF-1 signaling suppresses the innate and adaptive immune systems to evade immune attack by inducing the expression of immunosuppressive factors and immune checkpoint molecules, including vascular endothelial growth factor, prostaglandin E2 , and programmed death-ligand 1/programmed death-1. Moreover, HIF-1 blocks tumor-associated antigen presentation via major histocompatibility complex class I chain-related/natural killer group 2, member D signaling. Tumor-associated autophagy and the release of tumor-derived exosomes contribute to HIF-1-mediated immune evasion. This review focuses on recent findings on the potential mechanism(s) underlying the effect of hypoxia and HIF-1 signaling on tumor immune evasion in the hypoxic tumor microenvironment. The effects of HIF-1 on immune checkpoint molecules, immunosuppressive molecules, autophagy, and exosomes have been described. Additionally, the potential role of HIF-1 in the regulation of tumor-derived exosomes, as well as the roles of HIF-1 and exosomes in tumor evasion, are discussed. This study will contribute to our understanding of HIF-1-mediated tumor immune evasion, leading to the development of effective HIF-1-targeting drugs and immunotherapies.

The role of hypoxia-inducible factor 1 in tumor immune evasion.

Metastasis is the leading cause of death for cancer patients. During cancer progression, the initial detachment of cells from the primary tumor and the later colonization of a secondary organ are characterized as limiting steps for metastasis. Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are opposite dynamic multistep processes that enable these critical events in metastasis by altering the phenotype of cancer cells and improving their ability to migrate, invade and seed at distant organs. Among the molecular pathways that promote tumorigenesis in late-stage cancers, transforming growth factor-β (TGF-β) is described as an EMT master inducer by controlling different genes and proteins related to cytoskeleton assembly, cell-cell attachment and extracellular matrix remodeling. Still, despite the successful outcomes of different TGF-β pharmacological inhibitors in cell culture (in vitro) and animal models (in vivo), results in cancer clinical trials are poor or inconsistent at least, highlighting the existence of crucial components in human cancers that have not been properly explored. Here we review most recent findings to provide perspectives bridging the gap between on-target anti-TGF-β therapies in vitro and in pre-clinical models and the poor clinical outcomes in treating cancer patients. Specifically, we focus on (i) the dual roles of TGF-β signaling in cancer metastasis; (ii) dynamic signaling; (iii) functional differences of TGF-β free in solution vs. in exosomes; (iv) the regulatory effects of tumor microenvironment (TME) - particularly by cancer-associated fibroblasts - on TGF-β signaling pathway. Clearly identifying and establishing those missing links may provide strategies to revitalize and clinically improve the efficacy of TGF-β targeted therapies.

/pdf/on-target-anti-tgf-b-therapies-are-not-succeeding-in-g9qn1me81p.pdf

On-Target Anti-TGF-β Therapies Are Not Succeeding in Clinical Cancer Treatments: What Are Remaining Challenges?

Exosome is a nanoscale vesicle with a size range of 30-100 nm. It is secreted from cell to extracellular space by exocytosis after fusion of multivesicular body (MVB) (formed by endocytic vesicles) with plasma membrane. Exosome plays several important roles in cellular homeostasis and intercellular communications. During the last two decades, exosome has acquired a wide attention to explore its additional roles in various aspects of cell biology and function in several organ systems. For the kidney, several lines of evidence have demonstrated 1that exosome is involved in the renal physiology and pathogenic mechanisms of various kidney diseases/disorders. This article summarizes roles of the exosome as the potential source of biomarkers, pathogenic molecules, and therapeutic biologics that have been extensively investigated in many kidney diseases/disorders, including lupus nephritis (LN), other glomerular diseases, acute kidney injury (AKI), diabetic nephropathy (DN), as well as in the process of renal fibrosis and chronic kidney disease (CKD) progression, in addition to polycystic kidney disease (PKD), kidney transplantation, and renal cell carcinoma (RCC). Moreover, the most recent evidence has shown its emerging role in kidney stone disease (or nephrolithiasis), involving inflammasome activation and inflammatory cascade frequently found in kidney stone pathogenesis.

Roles for Exosome in Various Kidney Diseases and Disorders.

Identification of immunogenic tumor antigens that are efficiently processed and delivered by dendritic cells to prime the immune system and to induce an appropriate immune response is a research hotspot in the field of cancer vaccine development High biosafety is an additional demand Tumor-derived exosomes (TEXs) are nanosized lipid bilayer encapsulated vesicles that shuttle bioactive information to the tumor microenvironment facilitating tumor progression However, accumulating evidence points toward the capacity of TEXs to efficiently stimulate immune responses against tumors provided they are appropriately administered After briefly describing the function of exosomes in cancer biology and their communication with immune cells, we summarize in this review in vitro and preclinical studies eliciting the potency of TEXs in inducing effective anti-tumor responses and recently modified strategies further improving TEX-vaccination efficacy We interpret the available data as TEXs becoming a lead in cancer vaccination based on tumor antigen-selective high immunogenicity

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2020.1779991

Tumor-derived exosomes: the next generation of promising cell-free vaccines in cancer immunotherapy

// Yang Xia 1 , Qiongfang Zhang 2 , Quan Zhen 1 , Yan Zhao 3 , Nanjing Liu 3 , Ting Li 3 , Yanni Hao 3 , Yao Zhang 1 , Chunli Luo 3 and Xiaohou Wu 1 1 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China 2 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China 3 Key Laboratory of Diagnostics Medicine designated by the Ministry of Education, Chongqing Medical University, Chongqing 400016, China Correspondence to: Xiaohou Wu, email: wuxiaohou80@hotmail.com Keywords: exosome, clear cell renal cell carcinoma, natural killer, transforming growth factor-β1, tumor immune evasion Received: November 25, 2016      Accepted: February 15, 2017      Published: March 18, 2017 ABSTRACT Natural killer cells are the key components in tumor immunity and defects in function are necessary for tumor immune escape. Emerging studies on tumor cell-derived exosomes have shown the biological significance in tumor microenvironment, but the underlying role of exosomes in regulating natural killer cells functions in clear cell renal cell carcinoma patients remains unknown. Firstly, we precisely characterized the phenotype and function of natural killer cells in clear cell renal cell carcinoma patients vs healthy controls. With an inhibitory phenotype, tumor-infiltrating natural killer cells exhibited poor cytotoxic capacity and deficient potential to produce cytokines compared with natural killer cells from tumor margin tissue and non-tumor tissue. Next, we revealed that primary tumor cells trigged natural killer cell dysfunction in an exosome-dependent manner. Interestingly, exosomes from primary tumor cells were preferentially enriched with TGF-β1 which acted as important mediator of natural killer cell functional deficiency. In vitro culture of exosomes induced natural killer cell dysfunction mediated by activation of the TGF-β/SMAD signaling pathway, and abrogated by knockdown TGF-β. Our data indicate that exosomes from clear cell renal cell carcinoma induce natural killer cells dysfunction by regulating the TGF-β/SMAD pathway to evade innate immune surveillance.

Negative regulation of tumor-infiltrating NK cell in clear cell renal cell carcinoma patients through the exosomal pathway

Interleukin 6 induces cell proliferation of clear cell renal cell carcinoma by suppressing hepaCAM via the STAT3-dependent up-regulation of DNMT1 or DNMT3b.

Androgen receptor (AR) signaling is a major driver of prostate cancer (CaP). Although most therapies targeting AR are initially effective in CaP patients, drug resistance is inevitable, mainly because of the inappropriate re-activation of AR pathway. However, the underlying mechanisms remain largely unknown. Here, we found that phospholipase C epsilon (PLCɛ) was highly expressed in CaP samples, and was closely associated with AR signaling activities. PLCɛ depletion triggered enhanced autophagic activities via AMPK/ULK1 pathway, causing autophagy-mediated AR degradation and inhibition of AR nuclear translocation. This subsequently reduced AR signals in CaP and inhibited AR-driven cell migration/invasion. Furthermore, a positive correlation between PLCɛ and AR signaling activity was also observed in bicalutamide-resistant CaP samples and in AR-antagonist-resistant CaP cell models. PLCɛ depletion resulted in the failure to establish AR-antagonist-resistant CaP cell lines, and hindered the metastatic prowess of already established ones. These findings suggest that PLCɛ-mediated autophagic activity alteration is indispensible for the functionality of AR signaling and for CaP development.

/pdf/plce-maintains-the-functionality-of-ar-signaling-in-prostate-4buijuy78x.pdf

PLCɛ maintains the functionality of AR signaling in prostate cancer via an autophagy-dependent mechanism

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Negative regulation of tumor-infiltrating NK cell in clear cell renal cell carcinoma patients through the exosomal pathway

Interleukin 6 induces cell proliferation of clear cell renal cell carcinoma by suppressing hepaCAM via the STAT3-dependent up-regulation of DNMT1 or DNMT3b.

PLCɛ maintains the functionality of AR signaling in prostate cancer via an autophagy-dependent mechanism