Clinically Relevant Immune Responses against Cytomegalovirus: Implications for Precision Medicine

Immune responses to human cytomegalovirus (CMV) can be used to assess immune fitness in an individual. Further to its clinical significance in posttransplantation settings, emerging clinical and translational studies provide examples of immune correlates of protection pertaining to anti-CMV immune responses in the context of cancer or infectious diseases, e.g., tuberculosis. In this viewpoint, we provide a brief overview about CMV-directed immune reactivity and immune fitness in a clinical context and incorporate some of our own findings obtained from peripheral blood or tumour-infiltrating lymphocytes (TIL) from patients with advanced cancer. Observations in patients with solid cancers whose lesions contain both CMV and tumour antigen-specific T-cell subsets are highlighted, due to a possible CMV-associated “bystander” effect in amplifying local inflammation and subsequent tumour rejection. The role of tumour-associated antibodies recognising diverse CMV-derived epitopes is also discussed in light of anti-cancer immune responses. We discuss here the use of anti-CMV immune responses as a theranostic tool—combining immunodiagnostics with a personalised therapeutic potential—to improve treatment outcomes in oncological indications.

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Molecular and Biochemical Basis of Minocycline-Induced Hyperpigmentation—The Study on Normal Human Melanocytes Exposed to UVA and UVB Radiation

International Journal of Molecular Sciences ◽

10.3390/ijms22073755 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3755

Author(s):

Jakub Rok ◽

Zuzanna Rzepka ◽

Justyna Kowalska ◽

Klaudia Banach ◽

Artur Beberok ◽

...

Keyword(s):

Uv Radiation ◽

Therapeutic Potential ◽

Melanin Synthesis ◽

Uvb Radiation ◽

Biochemical Basis ◽

Skin Hyperpigmentation ◽

Human Melanocytes ◽

Anti Cancer ◽

Normal Human

Minocycline is a drug which induces skin hyperpigmentation. Its frequency reaches up to 50% of treated patients. The adverse effect diminishes the great therapeutic potential of minocycline, including antibacterial, neuroprotective, anti-inflammatory and anti-cancer actions. It is supposed that an elevated melanin level and drug accumulation in melanin-containing cells are related to skin hyperpigmentation. This study aimed to evaluate molecular and biochemical mechanism of minocycline-induced hyperpigmentation in human normal melanocytes, as well as the contribution of UV radiation to this side effect. The experiments involved the evaluation of cyto- and phototoxic potential of the drug using cell imaging with light and confocal microscopes as well as biochemical and molecular analysis of melanogenesis. We showed that minocycline induced melanin synthesis in epidermal melanocytes. The action was intensified by UV irradiation, especially with the UVB spectrum. Minocycline stimulated the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase (TYR) gene. Higher levels of melanin and increased activity of tyrosinase were also observed in treated cells. Moreover, minocycline triggered the supranuclear accumulation of tyrosinase, similar to UV radiation. The decreased level of premelanosome protein PMEL17 observed in all minocycline-treated cultures suggests disorder of the formation, maturation or distribution of melanosomes. The study revealed that minocycline itself was able to enhance melanin synthesis. The action was intensified by irradiation, especially with the UVB spectrum. Demonstrated results confirmed the potential role of melanin and UV radiation minocycline-induced skin hyperpigmentation.

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The Role of Yes-Associated Protein (YAP) in Regulating Programmed Death-Ligand 1 (PD-L1) in Thoracic Cancer

Biomedicines ◽

10.3390/biomedicines6040114 ◽

2018 ◽

Vol 6 (4) ◽

pp. 114 ◽

Cited By ~ 12

Author(s):

Ping-Chih Hsu ◽

Cheng-Ta Yang ◽

David Jablons ◽

Liang You

Keyword(s):

Immune Responses ◽

Immune Checkpoint ◽

T Cell Tolerance ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Anti Cancer ◽

Thoracic Cancer ◽

Future Work ◽

Human Nsclc

The programmed death-ligand 1(PD-L1)/PD-1 pathway is an immunological checkpoint in cancer cells. The binding of PD-L1 and PD-1 promotes T-cell tolerance and helps tumor cells escape from host immunity. Immunotherapy targeting the PD-L1/PD-1 axis has been developed as an anti-cancer therapy and used in treating advanced human non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Yes-associated protein (YAP) is a key mediator of the Hippo/YAP signaling pathway, and plays important roles in promoting cancer development, drug resistance and metastasis in human NSCLC and MPM. YAP has been suggested as a new therapeutic target in NSCLC and MPM. The role of YAP in regulating tumor immunity such as PD-L1 expression has just begun to be explored, and the correlation between YAP-induced tumorigenesis and host anti-tumor immune responses is not well known. Here, we review recent studies investigating the correlation between YAP and PD-L1 and demonstrating the mechanism by which YAP regulates PD-L1 expression in human NSCLC and MPM. Future work should focus on the interactions between Hippo/YAP signaling pathways and the immune checkpoint PD-L1/PD-1 pathway. The development of new synergistic drugs for immune checkpoint PD-L1/PD-1 blockade in NSCLC and MPM is warranted.

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The complex functions of microRNA-150 in allergy, autoimmunity and immune tolerance

AIMS Allergy and Immunology ◽

10.3934/allergy.2021016 ◽

2021 ◽

Vol 5 (4) ◽

pp. 195-221

Author(s):

Katarzyna Nazimek ◽

Keyword(s):

Immune Responses ◽

Immune Tolerance ◽

Therapeutic Potential ◽

Current Knowledge ◽

Signaling Cascades ◽

Cell Functions ◽

Regulatory Circuits ◽

Complex Functions ◽

Genetic Level

<abstract> <p>At present, special efforts are being made to develop the strategies allowing for activation of long-lasting antigen-specific immune tolerance in therapy of allergic and autoimmune diseases. Some of these therapeutic approaches are aimed at modulating cell functions at genetic level by using miRNA-based and miRNA-targeting treatments. Simultaneously, the crucial role of extracellular vesicles as natural miRNA conveyors is highlighted for induction of antigen-specific immune tolerance, especially that they appear to be easily manipulatable for therapeutic applications. Among other immune-related miRNAs, miR-150 is getting special attention as it is differently expressed by immune cells at various stages of their maturation and differentiation. In addition, miR-150 is involved in different signaling cascades orchestrating humoral and cell-mediated mechanisms of both innate and adaptive immune responses. Therefore, miR-150 is considered a master regulator of immunity in mammals. Currently, physiological miR-150-dependent regulatory circuits and causes of their malfunctioning that underlie the pathogenesis of allergic and autoimmune disorders are being unraveled. Thus, present review summarizes the current knowledge of the role of miR-150 in the pathogenesis and complications of these diseases. Furthermore, the involvement of miR-150 in regulation of immune responses to allergens and self-antigens and in induction of antigen-specific immune tolerance is discussed with the special emphasis on the therapeutic potential of this miRNA.</p> </abstract>

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The microbiota plays a critical role in the reactivity of lung immune components to innate ligands

10.1101/2020.10.19.345116 ◽

2020 ◽

Author(s):

Quentin Marquant ◽

Daphné Laubreton ◽

Carole Drajac ◽

Elliot Mathieu ◽

Edwige Bouguyon ◽

...

Keyword(s):

Immune Responses ◽

Critical Role ◽

Innate Immune ◽

Immune Reactivity ◽

Innate Immune Responses ◽

Plain Language ◽

Pulmonary Tissue ◽

Germ Free ◽

Syncytial Virus

AbstractThe microbiota contributes to shaping efficient and safe immune defenses in the gut. However, little is known about the role of the microbiota in the education of pulmonary innate immune responses. Here, we tested whether the endogenous microbiota can modulate reactivity of pulmonary tissue to pathogen stimuli by comparing the response of specific pathogen-free (SPF) and germ-free (GF) mice. Using SPF and GF mice intranasally exposed to lipopolysaccharide (LPS), a component of Gram-negative bacteria, we observed earlier and greater inflammation in the pulmonary compartment of GF mice than that of SPF mice. Toll-like receptor 4 (TLR4) was more abundantly expressed in the lungs of GF mice than those of SPF mice at steady state, which could predispose the innate immunity of GF mice to strongly react to environmental stimuli. Lung explants were stimulated with different TLR agonists or infected with the human airways pathogen, respiratory syncytial virus (RSV), resulting in greater inflammation under almost all conditions for the GF explants. Finally, alveolar macrophages (AM) from GF mice presented a higher innate immune response upon RSV infection than those of SPF mice. Overall, these data suggest that the presence of microbiota in SPF mice induced a process of innate immune tolerance in the lungs by a mechanism which remains to be elucidated. Our study represents a step forward to establishing the link between the microbiota and the immune reactivity of the lungs.Plain Language summaryMicrobiota represents an important partner of immunologic system at the interface between immune cells and epithelium. It is well known, notably in the gut, that the microbiota contributes in shaping efficient and safe defenses. However, little is known about the role of the microbiota in the education of pulmonary innate immune responses. In this study, we postulate that endogenous microbiota could dampen an excessive reactivity of pulmonary tissue to external stimuli. Thus, we sought to study the innate immune reaction switched on by viral or bacterial ligands in respiratory tract cells coming from mice with or without microbiota (germ-free condition, GF). Altogether, our results show a higher inflammatory reaction in GF condition. This study represents a step forward to better establish the link between the microbiota and the reactivity of the lung tissue. Not only these data demonstrate that the microbiota educates the pulmonary innate immune system, but also contributes the emerging concept of using respiratory commensal bacteria as potential next-generation probiotics to prevent susceptibility to respiratory diseases.

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Nitric Oxide and Immune Responses in Cancer: Searching for New Therapeutic Strategies

Current Medicinal Chemistry ◽

10.2174/0929867328666210707194543 ◽

2021 ◽

Vol 28 ◽

Author(s):

Adeleh Sahebnasagh ◽

Fatemeh Saghafi ◽

Sina Negintaji ◽

Tingyan Hu ◽

Mojtaba Shabani-Boroujeni ◽

...

Keyword(s):

Nitric Oxide ◽

Immune Responses ◽

Therapeutic Potential ◽

Relevant Literature ◽

Cochrane Library ◽

Signaling Molecule ◽

No Donors ◽

The Cochrane Library ◽

Oxide Synthase

: In recent years, there has been an increasing interest in understanding the mysterious functions of nitric oxide (NO) and how this pleiotropic signaling molecule contributes to tumorigenesis. This review attempts to expose and discuss the information available on the immunomodulatory role of NO in cancer and recent approaches to the role of NO donors in the area of immunotherapy. To address the goal, the following databases were searched to identify relevant literature concerning empirical evidence: The Cochrane Library, Pubmed, Medline, EMBASE from 1980 through March 2020. Valuable attempts have been made to develop distinctive NO-based cancer therapy. Although the data do not allow generalization, the evidence seems to indicate that low / moderate levels may favor tumorigenesis while higher levels would exert anti-tumor effects. In this sense, the use of NO donors could have an important therapeutic potential within immunotherapy, although there are still no clinical trials. The emerging understanding of NO-regulated immune responses in cancer may help unravel the recent features of this “double-edged sword” in cancer physiological and pathologic processes and its potential use as a therapeutic agent for cancer treatment. In short, in this review, we discuss the complex cellular mechanism in which NO, as a pleiotropic signaling molecule, participates in cancer pathophysiology. We also debate the dual role of NO in cancer and tumor progression, and clinical approaches for inducible nitric oxide synthase (iNOS) based therapy against cancer.

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Immunomodulatory Role of Microbial Surfactants, with Special Emphasis on Fish

International Journal of Molecular Sciences ◽

10.3390/ijms21197004 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7004

Author(s):

Sib Sankar Giri ◽

Hyoun Joong Kim ◽

Sang Guen Kim ◽

Sang Wha Kim ◽

Jun Kwon ◽

...

Keyword(s):

Surface Tension ◽

Wound Healing ◽

Immune Responses ◽

Food Industry ◽

Hydrophobic Compounds ◽

Anti Cancer ◽

Surface Active ◽

Novel Therapeutic ◽

Multifunctional Properties

Microbial surfactants (biosurfactants) are a broad category of surface-active biomolecules with multifunctional properties. They self-assemble in aqueous solutions and are adsorbed on various interfaces, causing a decrease in surface tension, as well as interfacial tension, solubilization of hydrophobic compounds, and low critical micellization concentrations. Microbial biosurfactants have been investigated and applied in several fields, including bioremediation, biodegradation, food industry, and cosmetics. Biosurfactants also exhibit anti-microbial, anti-biofilm, anti-cancer, anti-inflammatory, wound healing, and immunomodulatory activities. Recently, it has been reported that biosurfactants can increase the immune responses and disease resistance of fish. Among various microbial surfactants, lipopeptides, glycolipids, and phospholipids are predominantly investigated. This review presents the various immunological activities of biosurfactants, mainly glycolipids and lipopeptides. The applications of biosurfactants in aquaculture, as well as their immunomodulatory activities, that make them novel therapeutic candidates have been also discussed in this review.

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Role of Vector in Activation of T Cell Subsets in Immune Responses against the Secreted Transgene Product Factor IX

Molecular Therapy ◽

10.1006/mthe.2000.0032 ◽

2000 ◽

Vol 1 (3) ◽

pp. 225-235 ◽

Cited By ~ 103

Author(s):

Paul A. Fields ◽

Dariusz W. Kowalczyk ◽

Valder R. Arruda ◽

Elina Armstrong ◽

Mark L. McCleland ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Factor Ix ◽

T Cell Subsets ◽

Product Factor

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Immune Responses and Disease Enhancement during Respiratory Syncytial Virus Infection

Clinical Microbiology Reviews ◽

10.1128/cmr.18.3.541-555.2005 ◽

2005 ◽

Vol 18 (3) ◽

pp. 541-555 ◽

Cited By ~ 201

Author(s):

Peter J. M. Openshaw ◽

John S. Tregoning

Keyword(s):

Respiratory Syncytial Virus ◽

Animal Models ◽

Immune Responses ◽

Deep Understanding ◽

T Cell Subsets ◽

Chemokine Production ◽

Syncytial Virus ◽

Complex Deposition ◽

Major Factors

SUMMARY Respiratory syncytial virus (RSV) is one of the commonest and most troublesome viruses of infancy. It causes most cases of bronchiolitis, which is associated with wheezing in later childhood. In primary infection, the peak of disease typically coincides with the development of specific T- and B-cell responses, which seem, in large part, to be responsible for disease. Animal models clearly show that a range of immune responses can enhance disease severity, particularly after vaccination with formalin-inactivated RSV. Prior immune sensitization leads to exuberant chemokine production, an excessive cellular influx, and an overabundance of cytokines during RSV challenge. Under different circumstances, specific mediators and T-cell subsets and antibody-antigen immune complex deposition are incriminated as major factors in disease. Animal models of immune enhancement permit a deep understanding of the role of specific immune responses in RSV disease, assist in vaccine design, and indicate which immunomodulatory therapy might be beneficial to children with bronchiolitis.

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Integrated role of microRNA-30e-5p through targeting negative regulators of innate immune pathways during HBV infection and SLE

10.1101/2020.02.29.969014 ◽

2020 ◽

Author(s):

Richa Mishra ◽

Sanjana Bhattacharya ◽

Bhupendra S Rawat ◽

Ashish Kumar ◽

Akhilesh Kumar ◽

...

Keyword(s):

Innate Immunity ◽

Mouse Model ◽

Immune Responses ◽

Therapeutic Potential ◽

Innate Immune ◽

Locked Nucleic Acid ◽

Type I ◽

Innate Immune Responses ◽

Negative Regulators

AbstractPrecise regulation of innate immunity is crucial for the development of appropriate host immunity against microbial infections and the maintenance of immune homeostasis. The microRNAs are small non-coding RNA, post-transcriptional regulator of multiple genes and act as a rheostat for protein expression. Here, we identified microRNA(miR)-30e-5p (miR-30e) induced by the hepatitis B virus (HBV) and other viruses that act as a master regulator for innate immune responses. Moreover, pegylated type I interferons treatment to HBV patients for viral reduction also reduces the miRNA. Additionally, we have also shown the immuno-pathological effects of miR-30e in systemic lupus erythematous (SLE) patients and SLE mouse model. Mechanistically, the miR-30e targets multiple negative regulators namely TRIM38, TANK, ATG5, ATG12, BECN1, SOCS1, SOCS3 of innate immune signaling pathways and enhances innate immune responses. Furthermore, sequestering of endogenous miR-30e in PBMCs of SLE patients and SLE mouse model respectively by the introduction of antagomir and locked nucleic acid based inhibitor significantly reduces type I interferon and pro-inflammatory cytokines. Collectively, our study demonstrates the novel role of miR-30e in innate immunity and its prognostic and therapeutic potential in infectious and autoimmune diseases.

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CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4

International Journal of Molecular Sciences ◽

10.3390/ijms21218412 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8412

Author(s):

Jan Korbecki ◽

Klaudyna Kojder ◽

Donata Simińska ◽

Romuald Bohatyrewicz ◽

Izabela Gutowska ◽

...

Keyword(s):

Physiological Function ◽

Suppressor Cells ◽

Tumor Infiltrating Lymphocytes ◽

Myeloid Derived Suppressor Cells ◽

Anti Cancer ◽

Organ Specific ◽

Cc Chemokines ◽

Infiltrating Lymphocytes ◽

Tumor Associated Neutrophils

CC chemokines, a subfamily of 27 chemotactic cytokines, are a component of intercellular communication, which is crucial for the functioning of the tumor microenvironment. Although many individual chemokines have been well researched, there has been no comprehensive review presenting the role of all known human CC chemokines in the hallmarks of cancer, and this paper aims at filling this gap. The first part of this review discusses the importance of CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 in cancer. Here, we discuss the significance of CCL2 (MCP-1), CCL7, CCL8, CCL11, CCL13, CCL14, CCL15, CCL16, CCL17, CCL22, CCL23, CCL24, and CCL26. The presentation of each chemokine includes its physiological function and then the role in tumor, including proliferation, drug resistance, migration, invasion, and organ-specific metastasis of tumor cells, as well as the effects on angiogenesis and lymphangiogenesis. We also discuss the effects of each CC chemokine on the recruitment of cancer-associated cells to the tumor niche (eosinophils, myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), regulatory T cells (Treg)). On the other hand, we also present the anti-cancer properties of CC chemokines, consisting in the recruitment of tumor-infiltrating lymphocytes (TIL).

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