Assessment of adenosinergic activity of small extracellular vesicles in plasma of cancer patients and healthy donors.

The adenosinergic pathway converting endogenous ATP to adenosine (ADO) is a major immunosuppressive pathway in cancer. Emerging data indicate that plasma small extracellular vesicles (sEV) express CD39 and CD73 and produce ADO. Using a noninvasive, highly sensitive newly developed assay, metabolism of N-etheno-labeled eATP, eADP or eAMP by ecto-nucleotidases on the external surface of sEV was measured using high pressure liquid chromatography with fluorescence detection.

CD8 Tumor-Infiltrating Lymphocytes in Head and Neck Cancer: A Review.

CD8 tumor-infiltrating lymphocytes (TILs) are increasingly used in oncology as a prognostic and predictive tool to guide patient management. This review summarizes current literature on CD8 TILs in head and neck squamous cell carcinoma (SCC). Published meta-analyses and clinical trials evaluating CD8 TILs were analyzed.

Tumor-derived Exosomes and Antitumor Immunity.

Cancer immunotherapy, including immune checkpoint blockade, has been approved for treatment of patients with many cancer types. However, some patients fail to respond to immunotherapy, and emerging evidence indicates that tumor-derived exosomes (TEX) play a major role in reprogramming the host immune cells by inducing their dysfunction. Focusing on effector T cells, this review illustrates mechanisms of suppression that TEX use, thus promoting tumor escape from the host immune system.

Small extracellular vesicles as biomarkers of response in recurrent/metastatic HNSCC patients treated with immunotherapy.

Background: Biomarkers that effectively predict response to anti-PD-1 mAb therapy in cancer patients are an unmet need. We evaluated the utility of small extracellular vesicles (sEV) as biomarkers of response to immunotherapy in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients.

Methods: Plasma sEV were isolated from 24 R/M HNSCC patients prior to immunotherapy initiation.

Oncoviral Infections and Small Extracellular Vesicles.

Small extracellular vesicles (sEV) are small membrane-bound nanovesicles with a size range below 200 nm that are released by all types of cells. sEV carry a diverse cargo of proteins, lipids, glycans, and nucleic acids that mimic the content of producer cells. sEV mediate intercellular communication and play a key role in a broad variety of physiological and pathological conditions.

Assessment of ATP metabolism to adenosine by ecto-nucleotidases carried by tumor-derived small extracellular vesicles.

Immunosuppression is a hallmark of cancer progression. Tumor-derived small extracellular vesicles (sEV), also known as TEX, produce adenosine (ADO) and can mediate tumor-induced immunosuppression.Here, the ATP pathway of ADO production (ATP  ADP  AMP  ADO) by ecto-nucleotidases carried on the sEV surface was evaluated by a method using N-etheno-ATP (eATP) and N-etheno-AMP (eAMP) as substrates for enzymatic activity.

Small extracellular vesicles in plasma carry luminal cytokines that remain undetectable by antibody-based assays in cancer patients and healthy donors.

Background: Small (30-150nm) extracellular vesicles (sEV), also known as exosomes, play a key role in cell-to-cell signaling. They are produced by all cells, circulate freely and are present in all body fluids. Evidence indicates that cytokines are present on the surface and/or in the lumen of sEV.

Assessment of ATP Metabolism to Adenosine by Ecto-Nucleotidases Carried by Tumor-Derived Small Extracellular Vesicles.

Background: Immunosuppression is a hallmark of cancer progression. Tumor-derived small extracellular vesicles (sEV), also known as TEX, produce adenosine (ADO) and can mediate tumor-induced immunosuppression.

Methods: Here, the ATP pathway of ADO production (ATP◊ADP◊AMP◊ADO) by ecto-nucleotidases carried in sEV was evaluated by a novel method using N-etheno-ATP (eATP) and N-etheno-AMP (eAMP) as substrates.

Blast-Derived Small Extracellular Vesicles in the Plasma of Patients with Acute Myeloid Leukemia Predict Responses to Chemotherapy.

The small extracellular vesicles (sEV) accumulating in acute myeloid leukemia (AML) patients' plasma are mixtures of vesicles produced by leukemic and non-malignant cells. sEV originating from leukemia blasts could serve as potential non-invasive biomarkers of AML response to therapy. To isolate blast-derived sEV from patients' plasma, we developed a bioprinted microarray-based immunoassay using monoclonal antibodies (mAbs) specific for leukemia-associated antigens (LAAs) and mAbs specific for a mix of tetraspanins (CD9, CD63, and CD81).

Arginase-1 in Plasma-Derived Exosomes as Marker of Metastasis in Patients with Head and Neck Squamous Cell Carcinoma.

Immunoregulatory Arginase-1 (Arg-1) is present in the tumor microenvironment of solid tumors. Its association to clinicopathology and its prognostic impact are inconsistent among different tumor types and biological fluids. This study evaluated Arg-1 protein levels in tumors and the circulation of patients with head and neck squamous cell carcinoma (HNSCC) in relation to clinical stage and prognosis.

Immune capture and protein profiling of small extracellular vesicles from human plasma.

Extracellular vesicles (EVs), the key players in inter-cellular communication, are produced by all cell types and are present in all body fluids. Analysis of the proteome content is an important approach in structural and functional studies of these vesicles. EVs circulating in human plasma are heterogeneous in size, cellular origin, and functions.

Small EV in plasma of triple negative breast cancer patients induce intrinsic apoptosis in activated T cells.

Small extracellular vesicles (sEV) in TNBC patients' plasma promote T cell dysfunction and tumor progression. Here we show that tumor cell-derived exosomes (TEX) carrying surface PDL-1, PD-1, Fas, FasL, TRAIL, CTLA-4 and TGF-β1 induce apoptosis of CD8T and CD4T cells but spare B and NK cells. Inhibitors blocking TEX-induce receptor/ligand signals and TEX pretreatments with proteinase K or heat fail to prevent T cell apoptosis.

TGFβ carrying exosomes in plasma: potential biomarkers of cancer progression in patients with head and neck squamous cell carcinoma.

Objectives: Contributions of TGFβ to cancer progression are well documented. However, plasma TGFβ levels often do not correlate with clinicopathological data. We examine the role of TGFβ carried in exosomes isolated from murine and human plasma as a contributor to disease progression in head and neck squamous cell carcinoma (HNSCC).

Evaluating tumor cell- and T cell-derived extracellular vesicles as potential biomarkers of cancer and immune cell competence.

Introduction: Extracellular vesicles (EVs) produced by tumors, also called tumor-derived exosomes (TEX), have been implicated in inducing immune cell suppression and . The development of a novel category of noninvasive biomarkers for precision oncology remains an unmet need, and TEX emerge as a promising liquid tumor biopsy component.

Areas Covered: TEX play a critical role in monitoring cancer presence/progression and in reprograming of anti-tumor effector T cells to producers of EVs with pro-tumor activity.

Tumor gene signatures that correlate with release of extracellular vesicles shape the immune landscape in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinomas (HNSCCs) evade immune responses through multiple resistance mechanisms. Extracellular vesicles (EVs) released by the tumor and interacting with immune cells induce immune dysfunction and contribute to tumor progression. This study evaluates the clinical relevance and impact on anti-tumor immune responses of gene signatures expressed in HNSCC and associated with EV production/release.

Immunosuppressive functions of melanoma cell-derived exosomes in plasma of melanoma patients.

Tumor-derived exosomes (TEX) are a subset of small extracellular vesicles (sEV) present in all body fluids of patients with cancer. In plasma of patients with metastatic melanoma, numbers of exosomes produced by melanoma cells called MTEX are elevated. To study the role of MTEX in melanoma progression, immunoaffinity-based separation of MTEX from total plasma exosomes was performed.

TGFβ small extracellular vesicles from head and neck squamous cell carcinoma cells reprogram macrophages towards a pro-angiogenic phenotype.

Transforming growth factor β (TGFβ) is a major component of tumor-derived small extracellular vesicles (TEX) in cancer patients. Mechanisms utilized by TGFβ TEX to promote tumor growth and pro-tumor activities in the tumor microenvironment (TME) are largely unknown. TEX produced by head and neck squamous cell carcinoma (HNSCC) cell lines carried TGFβ and angiogenesis-promoting proteins.

Characteristics of Exosomes and the Vascular Landscape Regulate Exosome Sequestration by Peripheral Tissues and Brain.

Exosomes mediate intercellular communication, shuttling messages between cells and tissues. We explored whether exosome tissue sequestration is determined by the exosomes or the tissues using ten radiolabeled exosomes from human or murine, cancerous or noncancerous cell lines. We measured sequestration of these exosomes by the liver, kidney, spleen, and lung after intravenous injection into male CD-1 mice.

Proteomic and Metabolomic Profiles of T Cell-Derived Exosomes Isolated from Human Plasma.

Exosomes that are released by T cells are key messengers involved in immune regulation. However, the molecular profiling of these vesicles, which is necessary for understanding their functions, requires their isolation from a very heterogeneous mixture of extracellular vesicles that are present in the human plasma. It has been shown that exosomes that are produced by T cells could be isolated from plasma by immune capture using antibodies that target the CD3 antigen, which is a key component of the TCR complex that is present in all T lymphocytes.

NOX activation in reactive astrocytes regulates astrocytic LCN2 expression and neurodegeneration.

Reactive astrocytes (RA) secrete lipocalin-2 (LCN2) glycoprotein that regulates diverse cellular processes including cell death/survival, inflammation, iron delivery and cell differentiation. Elevated levels of LCN2 are considered as a biomarker of brain injury, however, the underlying regulatory mechanisms of its expression and release are not well understood. In this study, we investigated the role of astrocytic Na/H exchanger 1 (NHE1) in regulating reactive astrocyte LCN2 secretion and neurodegeneration after stroke.

Tumor-Infiltrating Lymphocytes and Their Role in Solid Tumor Progression.

Tumor-infiltrating lymphocytes (TIL) are an important component of the tumor environment. Their role in tumor growth and progression has been debated for decades. Today, emphasis has shifted to beneficial effects of TIL for the host and to therapies optimizing the benefits by reducing immune suppression in the tumor microenvironment.

Real world risk of infusion reactions and effectiveness of front-line obinutuzumab plus chlorambucil compared with other frontline treatments for chronic lymphocytic leukemia.

Background: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in North America. Previous studies have shown improved progression free survival (PFS) and response rates in unfit patients treated with obinutuzumab compared to other regimens. The aim of this study was to evaluate the obinutuzumab-chlorambucil regimen in the context of historical treatments and first-dose infusion reactions at CancerCare Manitoba (CCMB).