Nucleic Acid Sensing in the Tumor Vasculature

Endothelial cells form a powerful interface between tissues and immune cells. In fact, one of the underappreciated roles of endothelial cells is to orchestrate immune attention to specific sites. Tumor endothelial cells have a unique ability to dampen immune responses and thereby maintain an immunosuppressive microenvironment. Recent approaches to trigger immune responses in cancers have focused on activating nucleic acid sensors, such as cGAS-STING, in combination with immunotherapies. In this review, we present a case for targeting nucleic acid-sensing pathways within the tumor vasculature to invigorate tumor-immune responses. We introduce two specific nucleic acid sensors—the DNA sensor TREX1 and the RNA sensor RIG-I—and discuss their functional roles in the vasculature. Finally, we present perspectives on how these nucleic acid sensors in the tumor endothelium can be targeted in an antiangiogenic and immune activation context. We believe understanding the role of nucleic acid-sensing in the tumor vasculature can enhance our ability to design more effective therapies targeting the tumor microenvironment by co-opting both vascular and immune cell types.

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Nucleic Acid Sensing in the Tumor Vasculature

10.20944/preprints202107.0082.v1 ◽

2021 ◽

Author(s):

Adrian M. Baris ◽

Eugenia Fraile-Bethencourt ◽

Sudarshan Anand

Keyword(s):

Endothelial Cells ◽

Nucleic Acid ◽

Immune Responses ◽

Tumor Vasculature ◽

Functional Roles ◽

Tumor Endothelium ◽

Immunosuppressive Microenvironment ◽

Unique Ability ◽

Acid Sensors

Endothelial cells form a powerful interface between tissues and immune cells. In fact, one of the underappreciated roles of endothelial cells is to orchestrate immune attention to specific sites. Tumor endothelial cells have a unique ability to dampen the immune responses and thereby maintain an immunosuppressive microenvironment. Recent approaches to trigger immune responses in cancers have focused on activating nucleic acid sensors such as cGAS/STING in combination with immunotherapies. In this review, we present a case for targeting nucleic acid sensing pathways within the tumor vasculature to invigorate tumor immune responses. We introduce two specific nucleic acid sensors, the DNA sensor TREX1 and the RNA sensor RIG-I and discuss their functional roles in the vasculature. Finally, we present perspectives on how these nucleic acid sensors in the tumor endothelium can be targeted in an antiangiogenic and immune activation context. We believe understanding the role of nucleic acid sensing in the tumor vasculature can enhance our ability to design more effective therapies targeting the tumor microenvironment.

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Toll-Like Receptor-Based Strategies for Cancer Immunotherapy

Journal of Immunology Research ◽

10.1155/2021/9912188 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Saghar Pahlavanneshan ◽

Ali Sayadmanesh ◽

Hamidreza Ebrahimiyan ◽

Mohsen Basiri

Keyword(s):

Cancer Immunotherapy ◽

Immune Cells ◽

Immune Cell ◽

Cell Types ◽

Genetically Engineered ◽

Current Status ◽

Tlr Signaling ◽

Functional Roles ◽

Immunotherapy Of Cancer ◽

Signaling Components

Toll-like receptors (TLRs) are expressed and play multiple functional roles in a variety of immune cell types involved in tumor immunity. There are plenty of data on the pharmacological targeting of TLR signaling using agonist molecules that boost the antitumor immune response. A recent body of research has also demonstrated promising strategies for improving the cell-based immunotherapy methods by inducing TLR signaling. These strategies include systemic administration of TLR antagonist along with immune cell transfer and also genetic engineering of the immune cells using TLR signaling components to improve the function of genetically engineered immune cells such as chimeric antigen receptor-modified T cells. Here, we explore the current status of the cancer immunotherapy approaches based on manipulation of TLR signaling to provide a perspective of the underlying rationales and potential clinical applications. Altogether, reviewed publications suggest that TLRs make a potential target for the immunotherapy of cancer.

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Tumor Vasculature Targeted TNFα Therapy: Reversion of Microenvironment Anergy and Enhancement of the Anti-tumor Efficiency

Current Medicinal Chemistry ◽

10.2174/0929867325666180904121118 ◽

2020 ◽

Vol 27 (25) ◽

pp. 4233-4248

Author(s):

Enrica Balza ◽

Barbara Carnemolla ◽

Paola Orecchia ◽

Anna Rubartelli ◽

Alessandro Poggi ◽

...

Keyword(s):

Immune Responses ◽

Tumor Cells ◽

Stromal Cells ◽

Immune Cell ◽

Tumor Therapy ◽

Tumor Vasculature ◽

Chemotherapeutic Agents ◽

Tumor Vessel ◽

Adaptive Immune ◽

Selective Targeting

Tumor cells and tumor-associated stromal cells such as immune, endothelial and mesenchimal cells create a Tumor Microenvironment (TME) which allows tumor cell promotion, growth and dissemination while dampening the anti-tumor immune response. Efficient anti-tumor interventions have to keep into consideration the complexity of the TME and take advantage of immunotherapy and chemotherapy combined approaches. Thus, the aim of tumor therapy is to directly hit tumor cells and reverse endothelial and immune cell anergy. Selective targeting of tumor vasculature using TNFα-associated peptides or antibody fragments in association with chemotherapeutic agents, has been shown to exert a potent stimulatory effect on endothelial cells as well as on innate and adaptive immune responses. These drug combinations reducing the dose of single agents employed have led to minimize the associated side effects. In this review, we will analyze different TNFα-mediated tumor vesseltargeted therapies in both humans and tumor mouse models, with emphasis on the role played by the cross-talk between natural killer and dendritic cells and on the ability of TNFα to trigger tumor vessel activation and normalization. The improvement of the TNFα-based therapy with anti-angiogenic immunomodulatory drugs that may convert the TME from immunosuppressive to immunostimulant, will be discussed as well.

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Allogeneic Antigen Composition for Preparing Universal Cancer Vaccines

Journal of Immunology Research ◽

10.1155/2016/5031529 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Petr G. Lokhov ◽

Elena E. Balashova

Keyword(s):

Endothelial Cells ◽

Vaccine Development ◽

Present Report ◽

Tumor Vasculature ◽

Target Cells ◽

Human Endothelial Cells ◽

Cell Surface Antigens ◽

Tumor Endothelium ◽

Natural Target

Recently it was demonstrated that tumors induce specific changes to the surface of human endothelial cells thereby providing the basis for designing endothelial cell-based vaccines that directly target antigens expressed by the tumor endothelium. The present report extends these studiesin vitroby investigating the efficacy of allogeneic antigens with regard to their ability to target immune responses against the tumor vasculature since alloantigens simplify vaccine development and implementation in clinical practice. We demonstrated that allogeneic SANTAVAC (Set of All Natural Target Antigens for Vaccination Against Cancer), which presents a specifically prepared composition of cell surface antigens from tumor-stimulated endothelial cells, allows targeting of the tumor vasculature with efficacy of 17, where efficacy represents the killing rate of target cells before normal cells are adversely affected, and efficacy of 60, where efficacy represents the fold decrease in the number of target cells and directly relates to tumor growth arrest. These data suggest that allogeneic SANTAVAC may be considered an antigenic composition that following administration in the presence of respective adjuvants may be clinically tested as a therapeutic or prophylactic universal cancer vaccine without adverse side effects to the normal vasculature.

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A Catalogus Immune Muris of the mouse immune responses to diverse pathogens

Cell Death and Disease ◽

10.1038/s41419-021-04075-y ◽

2021 ◽

Vol 12 (9) ◽

Author(s):

Céline Barlier ◽

Diego Barriales ◽

Alexey Samosyuk ◽

Sascha Jung ◽

Srikanth Ravichandran ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Biomedical Applications ◽

Immune Cell ◽

Cell Types ◽

Computational Method ◽

Functional Responses ◽

Macrophage Cell ◽

Functional States

AbstractImmunomodulation strategies are crucial for several biomedical applications. However, the immune system is highly heterogeneous and its functional responses to infections remains elusive. Indeed, the characterization of immune response particularities to different pathogens is needed to identify immunomodulatory candidates. To address this issue, we compiled a comprehensive map of functional immune cell states of mouse in response to 12 pathogens. To create this atlas, we developed a single-cell-based computational method that partitions heterogeneous cell types into functionally distinct states and simultaneously identifies modules of functionally relevant genes characterizing them. We identified 295 functional states using 114 datasets of six immune cell types, creating a Catalogus Immune Muris. As a result, we found common as well as pathogen-specific functional states and experimentally characterized the function of an unknown macrophage cell state that modulates the response to Salmonella Typhimurium infection. Thus, we expect our Catalogus Immune Muris to be an important resource for studies aiming at discovering new immunomodulatory candidates.

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Aging-Related Cellular, Structural and Functional Changes in the Lymph Nodes: A Significant Component of Immunosenescence? An Overview

Cells ◽

10.3390/cells10113148 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3148

Author(s):

Marta Cakala-Jakimowicz ◽

Paulina Kolodziej-Wojnar ◽

Monika Puzianowska-Kuznicka

Keyword(s):

Immune System ◽

Immune Responses ◽

Lymph Nodes ◽

Immune Cell ◽

Humoral Response ◽

The Elderly ◽

Cell Types ◽

Functional Changes ◽

B Cell Homeostasis

Aging affects all tissues and organs. Aging of the immune system results in the severe disruption of its functions, leading to an increased susceptibility to infections, an increase in autoimmune disorders and cancer incidence, and a decreased response to vaccines. Lymph nodes are precisely organized structures of the peripheral lymphoid organs and are the key sites coordinating innate and long-term adaptive immune responses to external antigens and vaccines. They are also involved in immune tolerance. The aging of lymph nodes results in decreased cell transport to and within the nodes, a disturbance in the structure and organization of nodal zones, incorrect location of individual immune cell types and impaired intercellular interactions, as well as changes in the production of adequate amounts of chemokines and cytokines necessary for immune cell proliferation, survival and function, impaired naïve T- and B-cell homeostasis, and a diminished long-term humoral response. Understanding the causes of these stromal and lymphoid microenvironment changes in the lymph nodes that cause the aging-related dysfunction of the immune system can help to improve long-term immune responses and the effectiveness of vaccines in the elderly.

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Autologous humanized mouse models of iPSC-derived tumors allow for the evaluation and modulation of cancer-immune cell interactions

10.1101/2021.04.02.437733 ◽

2021 ◽

Author(s):

Gaël Moquin-Beaudry ◽

Basma Benabdallah ◽

Damien Maggiorani ◽

Oanh Le ◽

Yuanyi Li ◽

...

Keyword(s):

Drug Development ◽

Tumor Cell ◽

Cell Lines ◽

Immune Cells ◽

Immune Cell ◽

Cell Types ◽

Cell Interactions ◽

Humanized Mice ◽

Immunosuppressive Microenvironment ◽

Cancer Immunotherapies

ABSTRACTModeling the tumor-immune cell interactions in humanized mice is complex and limits drug development. Here, we generated easily accessible tumor models by transforming either primary skin fibroblasts or iPSC-derived cell lines injected in immune-deficient mice reconstituted with human autologous immune cells. Our results showed that either fibroblastic, hepatic or neural tumors were all efficiently infiltrated and partially or totally rejected by autologous immune cells in humanized mice. Characterization of tumor immune infiltrates revealed high expression levels of the dysfunction markers Tim3 and PD-1 in T cells and an enrichment in regulatory T cell suggesting rapid establishment of an immunosuppressive microenvironment. Inhibition of PD-1 by Nivolumab in humanized mice resulted in an increased immune cell infiltration and a slight decrease in tumor growth. We expect these versatile and accessible cancer models will facilitate preclinical studies and the evaluation of autologous cancer immunotherapies across a range of different tumor cell types.SIGNIFICANCE STATEMENTPreclinical models capable of providing an environment where human tumors are confronted with autologous immune cells are not easily accessible and limit drug development. As an alternative we generated genetically-defined tumor cell lines from primary and iPSC-derived cells for the evaluation of cancer-immune cell interactions in autologous humanized mice.

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Immunopathology of Postprimary Tuberculosis: Increased T-Regulatory Cells and DEC-205-Positive Foamy Macrophages in Cavitary Lesions

Clinical and Developmental Immunology ◽

10.1155/2011/307631 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 34

Author(s):

Kerry J. Welsh ◽

Semyon A. Risin ◽

Jeffrey K. Actor ◽

Robert L. Hunter

Keyword(s):

Endothelial Cells ◽

T Regulatory Cells ◽

Immune Cell ◽

Cell Types ◽

Cell Marker ◽

Regulatory Cells ◽

Immunohistochemical Studies ◽

Mycobacterial Antigens ◽

Foamy Macrophages ◽

Lipid Pneumonia

Postprimary tuberculosis occurs in immunocompetent people infected withMycobacterium tuberculosis. It is restricted to the lung and accounts for 80% of cases and nearly 100% of transmission. Little is known about the immunopathology of postprimary tuberculosis due to limited availability of specimens. Tissues from 30 autopsy cases of pulmonary tuberculosis were located. Sections of characteristic lesions of caseating granulomas, lipid pneumonia, and cavitary stages of postprimary disease were selected for immunohistochemical studies of macrophages, lymphocytes, endothelial cells, and mycobacterial antigens. A higher percentage of cells in lipid pneumonia (36.1%) and cavitary lesions (27.8%) were positive for the dendritic cell marker DEC-205, compared to granulomas (9.0%,P<.05). Cavities contained significantly more T-regulatory cells (14.8%) than found in lipid pneumonia (5.2%) or granulomas (4.8%). Distribution of the immune cell types may contribute to the inability of the immune system to eradicate tuberculosis.

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SLAM Family Receptor Signaling in Viral Infections: HIV and Beyond

Vaccines ◽

10.3390/vaccines7040184 ◽

2019 ◽

Vol 7 (4) ◽

pp. 184

Author(s):

O’Connell ◽

Amalfitano ◽

Aldhamen

Keyword(s):

Immune System ◽

Immune Responses ◽

Viral Infections ◽

Immune Cell ◽

Adaptor Protein ◽

Adaptor Proteins ◽

Cell Types ◽

Receptor Signaling ◽

Slam Family ◽

Signaling Lymphocytic Activation Molecule

The signaling lymphocytic activation molecule (SLAM) family of receptors are expressed on the majority of immune cells. These receptors often serve as self-ligands, and play important roles in cellular communication and adhesion, thus modulating immune responses. SLAM family receptor signaling is differentially regulated in various immune cell types, with responses generally being determined by the presence or absence of two SLAM family adaptor proteins—Ewing’s sarcoma-associated transcript 2 (EAT-2) and SLAM-associated adaptor protein (SAP). In addition to serving as direct regulators of the immune system, certain SLAM family members have also been identified as direct targets for specific microbes and viruses. Here, we will discuss the known roles for these receptors in the setting of viral infection, with special emphasis placed on HIV infection. Because HIV causes such complex dysregulation of the immune system, studies of the roles for SLAM family receptors in this context are particularly exciting.

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MIF-Dependent Control of Tumor Immunity

Frontiers in Immunology ◽

10.3389/fimmu.2020.609948 ◽

2020 ◽

Vol 11 ◽

Author(s):

Jordan T. Noe ◽

Robert A. Mitchell

Keyword(s):

Immune Responses ◽

Malignant Disease ◽

Immune Cell ◽

Cell Types ◽

Innate Immune Responses ◽

Adaptive Immune ◽

Intracellular Proteins ◽

Intracellular Compartments ◽

Immune Tolerant ◽

Pleiotropic Functions

Initially identified as a T lymphocyte-elicited inhibitor of macrophage motility, macrophage migration inhibitory factor (MIF) has since been found to be expressed by nearly every immune cell type examined and overexpressed in most solid and hematogenous malignant cancers. It is localized to both extracellular and intracellular compartments and physically interacts with more than a dozen different cell surface and intracellular proteins. Although classically associated with and characterized as a mediator of pro-inflammatory innate immune responses, more recent studies demonstrate that, in malignant disease settings, MIF contributes to anti-inflammatory, immune evasive, and immune tolerant phenotypes in both innate and adaptive immune cell types. This review will summarize the studies describing MIF in tumor-specific innate and adaptive immune responses and attempt to reconcile these various pleiotropic functions in normal physiology.

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