Modulation of the Vascular-Immune Environment in Metastatic Cancer

Advanced metastatic cancer is rarely curable. While immunotherapy has changed the oncological landscape profoundly, cure in metastatic disease remains the exception. Tumor blood vessels are crucial regulators of tumor perfusion, immune cell influx and metastatic dissemination. Indeed, vascular hyperpermeability is a key feature of primary tumors, the pre-metastatic niche in host tissue and overt metastases at secondary sites. Combining anti-angiogenesis and immune therapies may therefore unlock synergistic effects by inducing a stabilized vascular network permissive for effector T cell trafficking and function. However, anti-angiogenesis therapies, as currently applied, are hampered by intrinsic or adaptive resistance mechanisms at primary and distant tumor sites. In particular, heterogeneous vascular and immune environments which can arise in metastatic lesions of the same individual pose significant challenges for currently approved drugs. Thus, more consideration needs to be given to tailoring new combinations of vascular and immunotherapies, including dosage and timing regimens to specific disease microenvironments.

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A silicon nanomembrane platform for the visualization of immune cell trafficking across the human blood–brain barrier under flow

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18820584 ◽

2018 ◽

Vol 39 (3) ◽

pp. 395-410 ◽

Cited By ~ 16

Author(s):

Adrien Mossu ◽

Maria Rosito ◽

Tejas Khire ◽

Hung Li Chung ◽

Hideaki Nishihara ◽

...

Keyword(s):

Blood Brain Barrier ◽

Immune Cell ◽

Metastatic Cancer ◽

Neurovascular Unit ◽

Barrier Properties ◽

Brain Barrier ◽

Cell Trafficking ◽

Physiological Flow ◽

Blood Brain

Here we report on the development of a breakthrough microfluidic human in vitro cerebrovascular barrier (CVB) model featuring stem cell-derived brain-like endothelial cells (BLECs) and nanoporous silicon nitride (NPN) membranes (µSiM-CVB). The nanoscale thinness of NPN membranes combined with their high permeability and optical transparency makes them an ideal scaffold for the assembly of an in vitro microfluidic model of the blood–brain barrier (BBB) featuring cellular elements of the neurovascular unit (NVU). Dual-chamber devices divided by NPN membranes yield tight barrier properties in BLECs and allow an abluminal pericyte-co-culture to be replaced with pericyte-conditioned media. With the benefit of physiological flow and superior imaging quality, the µSiM-CVB platform captures each phase of the multi-step T-cell migration across the BBB in live cell imaging. The small volume of <100 µL of the µSiM-CVB will enable in vitro investigations of rare patient-derived immune cells with the human BBB. The µSiM-CVB is a breakthrough in vitro human BBB model to enable live and high-quality imaging of human immune cell interactions with the BBB under physiological flow. We expect it to become a valuable new tool for the study of cerebrovascular pathologies ranging from neuroinflammation to metastatic cancer.

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Characteristics of the Tumor Microenvironment That Influence Immune Cell Functions: Hypoxia, Oxidative Stress, Metabolic Alterations

Cancers ◽

10.3390/cancers12123802 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3802 ◽

Cited By ~ 1

Author(s):

Ryan C. Augustin ◽

Greg M. Delgoffe ◽

Yana G. Najjar

Keyword(s):

Oxidative Stress ◽

Tumor Microenvironment ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Tumor Infiltrating Lymphocytes ◽

Resistance Mechanisms ◽

Cell Trafficking ◽

Effective Response ◽

Cell Functions ◽

Cellular Energetics

Immunotherapy (IMT) is now a core component of cancer treatment, however, many patients do not respond to these novel therapies. Investigating the resistance mechanisms behind this differential response is now a critical area of research. Immune-based therapies, particularly immune checkpoint inhibitors (ICI), rely on a robust infiltration of T-cells into the tumor microenvironment (TME) for an effective response. While early efforts relied on quantifying tumor infiltrating lymphocytes (TIL) in the TME, characterizing the functional quality and degree of TIL exhaustion correlates more strongly with ICI response. Even with sufficient TME infiltration, immune cells face a harsh metabolic environment that can significantly impair effector function. These tumor-mediated metabolic perturbations include hypoxia, oxidative stress, and metabolites of cellular energetics. Primarily through HIF-1-dependent processes, hypoxia invokes an immunosuppressive phenotype via altered molecular markers, immune cell trafficking, and angiogenesis. Additionally, oxidative stress can promote lipid peroxidation, ER stress, and Treg dysfunction, all associated with immune dysregulation. Finally, the metabolic byproducts of lipids, amino acids, glucose, and cellular energetics are associated with immunosuppression and ICI resistance. This review will explore these biochemical pathways linked to immune cell dysfunction in the TME and highlight potential adjunctive therapies to be used alongside current IMT.

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Innate Immune Cell Trafficking and Function During Sterile Inflammation of the Liver

Gastroenterology ◽

10.1053/j.gastro.2016.09.048 ◽

2016 ◽

Vol 151 (6) ◽

pp. 1087-1095 ◽

Cited By ~ 39

Author(s):

Braedon McDonald ◽

Paul Kubes

Keyword(s):

Immune Cell ◽

Innate Immune ◽

Innate Immune Cell ◽

Sterile Inflammation ◽

Cell Trafficking ◽

Immune Cell Trafficking ◽

And Function

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Lymphatic Connexins and Pannexins in Health and Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22115734 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5734

Author(s):

Avigail Ehrlich ◽

Filippo Molica ◽

Aurélie Hautefort ◽

Brenda R. Kwak

Keyword(s):

Lymphatic System ◽

Immune Cell ◽

Current Knowledge ◽

Extracellular Fluid ◽

Cell Trafficking ◽

Secondary Lymphedema ◽

Transmembrane Channel ◽

Dietary Nutrient ◽

Lymphatic Vasculature ◽

And Function

This review highlights current knowledge on the expression and function of connexins and pannexins, transmembrane channel proteins that play an important role in intercellular communication, in both the developing and mature lymphatic vasculature. A particular focus is given to the involvement of these proteins in functions of the healthy lymphatic system. We describe their influence on the maintenance of extracellular fluid homeostasis, immune cell trafficking to draining lymph nodes and dietary nutrient absorption by intestinal villi. Moreover, new insights into connexin mutations in primary and secondary lymphedema as well as on the implication of lymphatic connexins and pannexins in acquired cardiovascular diseases are discussed, allowing for a better understanding of the role of these proteins in pathologies linked to dysfunctions in the lymphatic system.

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The role of lymphatics in intestinal inflammation

Inflammation and Regeneration ◽

10.1186/s41232-021-00175-6 ◽

2021 ◽

Vol 41 (1) ◽

Cited By ~ 1

Author(s):

Ryota Hokari ◽

Akira Tomioka

Keyword(s):

Immune Cell ◽

Intestinal Inflammation ◽

Inflammatory Diseases ◽

Dietary Lipid ◽

Peripheral Tolerance ◽

Lipid Absorption ◽

Lymphoid Tissues ◽

Cell Trafficking ◽

Lymphocyte Migration ◽

And Function

AbstractThe lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn’s disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer’s disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.

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An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma

10.1101/2020.03.17.990903 ◽

2020 ◽

Author(s):

Katherine E Baxter ◽

Christiano Tanese de Souza ◽

Lee-Hwa Tai ◽

Pasha Yaghini ◽

Manijeh Daneshmand ◽

...

Keyword(s):

Murine Model ◽

Immune Cell ◽

Therapeutic Benefit ◽

Treatment Modalities ◽

Ductal Adenocarcinoma ◽

Primary Tumors ◽

Immune Phenotyping ◽

Immunocompetent Mice ◽

And Function ◽

Post Implantation

AbstractBackgroundAlthough surgery provides the greatest therapeutic benefit to eligible pancreatic ductal adenocarcinoma (PDAC) patients it does not significantly improve survival for the majority of patients. Unfortunately our understanding of the therapeutic benefit of combining surgery with different treatment modalities including promising immunotherapeutics is limited by the current lack of easily adopted surgical models. The purpose of this study was to develop a surgically resectable model of PDAC in immunocompetent mice for use in preclinical investigations.Materials and MethodsSurgically resectable orthotopic tumors were generated by injecting Pan02 cells into the tail of the pancreas. Fifteen days post implantation the primary tumors and tail of the pancreas were resected by laparotomy while preserving the spleen. Splenic function, tumor growth, immune phenotyping and survival were assessed following surgical resection of the primary tumor mass.ResultsAs expected orthotopic tumor implants recapitulated many of the major histological hallmarks of PDAC including disrupted lobular structure and vascular invasion. Preservation of splenic immune cell viability and function was not associated with improved survival following surgery alone. However, pre-operative vaccination with GVAX was associated with improved survival which was not impacted by surgery.ConclusionThis represents the first murine model of surgically resectable murine model of PDAC which recapitulates known pathological hallmarks of human disease in an immune competent model while allowing spleen preservation. This relatively simple and easily adopted approach provides an ideal platform to examine the efficacy of potential immunotherapy combinations for PDAC surgery patients.

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Harnessing tumor immune ecosystem dynamics to personalize radiotherapy

10.1101/2020.02.11.944512 ◽

2020 ◽

Cited By ~ 2

Author(s):

G. Daniel Grass ◽

Juan C.L. Alfonso ◽

Eric Welsh ◽

Kamran A. Ahmed ◽

Jamie K. Teer ◽

...

Keyword(s):

Immune Cell ◽

Ecosystem Dynamics ◽

Primary Tumors ◽

Lung Cancer Patients ◽

Intrinsic Radiosensitivity ◽

Immune Therapies ◽

Patient Responses ◽

Dynamic Relationships ◽

The Relationship ◽

Improve Patient

AbstractRadiotherapy is a pillar of cancer care and augments the response to immunotherapies. However, little is known regarding the relationships between the tumor immune ecosystem (TIES) and intrinsic radiosensitivity, and a pressing question in oncology is how to optimize radiotherapy to improve patient responses to immune therapies. To address this challenge, we profiled over 10,000 primary tumors for their metrics of radiosensitivity and immune cell infiltrate (ICI), and applied a new integrated in silico model that mimics the dynamic relationships between tumor growth, ICI flux and the response to radiation. We then validated this model with a separate cohort of 59 lung cancer patients treated with radiotherapy. These analyses explain radiation response based on its effect on the TIES and quantifies the likelihood that radiation can promote a shift to anti-tumor immunity. Dynamic modeling of the relationship between tumor radiosensitivity and the TIES may provide opportunity to personalize combined radiation and immunotherapy approaches.

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Lymphatic Clearance of Immune Cells in Cardiovascular Disease

Cells ◽

10.3390/cells10102594 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2594

Author(s):

Christophe Ravaud ◽

Nikita Ved ◽

David G. Jackson ◽

Joaquim Miguel Vieira ◽

Paul R. Riley

Keyword(s):

Immune Cells ◽

Lymphatic System ◽

Immune Cell ◽

Heart Function ◽

Cell Trafficking ◽

Tissue Fluid ◽

Lymphatic Endothelium ◽

Cell Clearance ◽

Cardiac Outcome ◽

And Function

Recent advances in our understanding of the lymphatic system, its function, development, and role in pathophysiology have changed our views on its importance. Historically thought to be solely involved in the transport of tissue fluid, lipids, and immune cells, the lymphatic system displays great heterogeneity and plasticity and is actively involved in immune cell regulation. Interference in any of these processes can be deleterious, both at the developmental and adult level. Preclinical studies into the cardiac lymphatic system have shown that invoking lymphangiogenesis and enhancing immune cell trafficking in ischaemic hearts can reduce myocardial oedema, reduce inflammation, and improve cardiac outcome. Understanding how immune cells and the lymphatic endothelium interact is also vital to understanding how the lymphatic vascular network can be manipulated to improve immune cell clearance. In this Review, we examine the different types of immune cells involved in fibrotic repair following myocardial infarction. We also discuss the development and function of the cardiac lymphatic vasculature and how some immune cells interact with the lymphatic endothelium in the heart. Finally, we establish how promoting lymphangiogenesis is now a prime therapeutic target for reducing immune cell persistence, inflammation, and oedema to restore heart function in ischaemic heart disease.

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