scholarly journals NF-κB and Its Role in Checkpoint Control

2020 ◽  
Vol 21 (11) ◽  
pp. 3949 ◽  
Author(s):  
Annika C. Betzler ◽  
Marie-Nicole Theodoraki ◽  
Patrick J. Schuler ◽  
Johannes Döscher ◽  
Simon Laban ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Therapeutic Potential ◽  
Nuclear Factor Κb ◽  
Immune Checkpoint Blockade ◽  
Nuclear Factor ◽  
Checkpoint Control ◽  
Therapeutic Approaches

Nuclear factor-κB (NF-κB) has been described as one of the most important molecules linking inflammation to cancer. More recently, it has become clear that NF-κB is also involved in the regulation of immune checkpoint expression. Therapeutic approaches targeting immune checkpoint molecules, enabling the immune system to initiate immune responses against tumor cells, constitute a key breakthrough in cancer treatment. This review discusses recent evidence for an association of NF-κB and immune checkpoint expression and examines the therapeutic potential of inhibitors targeting either NF-κB directly or molecules involved in NF-κB regulation in combination with immune checkpoint blockade.

scholarly journals Targeting the ubiquitination/deubiquitination process to regulate immune checkpoint pathways

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Jiaxin Liu ◽  
Yicheng Cheng ◽  
Ming Zheng ◽  
Bingxiao Yuan ◽  
Zimu Wang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Biological Activities ◽  
Immune Surveillance ◽  
Immune Checkpoint Blockade ◽  
The Body ◽  
Immune Checkpoints ◽  
Immune Homeostasis ◽  
Innate And Adaptive Immunity

AbstractThe immune system initiates robust immune responses to defend against invading pathogens or tumor cells and protect the body from damage, thus acting as a fortress of the body. However, excessive responses cause detrimental effects, such as inflammation and autoimmune diseases. To balance the immune responses and maintain immune homeostasis, there are immune checkpoints to terminate overwhelmed immune responses. Pathogens and tumor cells can also exploit immune checkpoint pathways to suppress immune responses, thus escaping immune surveillance. As a consequence, therapeutic antibodies that target immune checkpoints have made great breakthroughs, in particular for cancer treatment. While the overall efficacy of immune checkpoint blockade (ICB) is unsatisfactory since only a small group of patients benefited from ICB treatment. Hence, there is a strong need to search for other targets that improve the efficacy of ICB. Ubiquitination is a highly conserved process which participates in numerous biological activities, including innate and adaptive immunity. A growing body of evidence emphasizes the importance of ubiquitination and its reverse process, deubiquitination, on the regulation of immune responses, providing the rational of simultaneous targeting of immune checkpoints and ubiquitination/deubiquitination pathways to enhance the therapeutic efficacy. Our review will summarize the latest findings of ubiquitination/deubiquitination pathways for anti-tumor immunity, and discuss therapeutic significance of targeting ubiquitination/deubiquitination pathways in the future of immunotherapy.

Potential immunotherapy for Alzheimer disease and age-related dementia

2019 ◽  
Vol 21 (1) ◽  
pp. 21-25 ◽  
Keyword(s):  
Immune System ◽  
Alzheimer Disease ◽  
Cross Talk ◽  
Immune Checkpoint ◽  
Short Review ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Approach ◽  
Age Related ◽  
The Brain

Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain's pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain's disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

Potential immunotherapy for Alzheimer disease and age-related dementia

2019 ◽  
Vol 21 (1) ◽  
pp. 21-25 ◽  
Keyword(s):  
Immune System ◽  
Alzheimer Disease ◽  
Cross Talk ◽  
Immune Checkpoint ◽  
Short Review ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Approach ◽  
Age Related ◽  
The Brain

Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain’s pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain’s disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

scholarly journals Rethinking immune checkpoint blockade: ‘Beyond the T cell’

2021 ◽  
Vol 9 (1) ◽  
pp. e001460 ◽  
Author(s):  
Xiuting Liu ◽  
Graham D Hogg ◽  
David G DeNardo
Keyword(s):  
Immune System ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

scholarly journals The Next-Generation of Combination Cancer Immunotherapy: Epigenetic Immunomodulators Transmogrify Immune Training to Enhance Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3596
Author(s):  
Reza Bayat Mokhtari ◽  
Manpreet Sambi ◽  
Bessi Qorri ◽  
Narges Baluch ◽  
Neda Ashayeri ◽  
...  
Keyword(s):  
Immune System ◽  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Tumor Antigens ◽  
Response Rates ◽  
Viral Proteins ◽  
Tumor Rejection ◽  
Therapeutic Approaches ◽  
Patient Response ◽  
Specific Antigens

Cancer immunotherapy harnesses the immune system by targeting tumor cells that express antigens recognized by immune system cells, thus leading to tumor rejection. These tumor-associated antigens include tumor-specific shared antigens, differentiation antigens, protein products of mutated genes and rearrangements unique to tumor cells, overexpressed tissue-specific antigens, and exogenous viral proteins. However, the development of effective therapeutic approaches has proven difficult, mainly because these tumor antigens are shielded, and cells primarily express self-derived antigens. Despite innovative and notable advances in immunotherapy, challenges associated with variable patient response rates and efficacy on select tumors minimize the overall effectiveness of immunotherapy. Variations observed in response rates to immunotherapy are due to multiple factors, including adaptative resistance, competency, and a diversity of individual immune systems, including cancer stem cells in the tumor microenvironment, composition of the gut microbiota, and broad limitations of current immunotherapeutic approaches. New approaches are positioned to improve the immune response and increase the efficacy of immunotherapies, highlighting the challenges that the current global COVID-19 pandemic places on the present state of immunotherapy.

scholarly journals Unlocking the Potential of Vaccines Built on Messenger RNA

2021 ◽  
pp. 160-197
Author(s):  
Elena Locci ◽  
Silvia Raymond
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Side Effects ◽  
Immune Responses ◽  
Messenger Rna ◽  
Healthy Tissue ◽  
Therapeutic Approaches ◽  
Inflammatory Reactions ◽  
Discontinuation Of Treatment ◽  
Keywords Cancer

In recent years, immunotherapy has revolutionized the treatment of cancer; however, inflammatory reactions in healthy tissues often have side effects that can be serious and lead to permanent discontinuation of treatment. This toxicity is not yet well understood and is a major obstacle to the use of immunotherapy. When the immune system is so severely activated, the resulting inflammatory reaction can have detrimental effects and sometimes serious damage to healthy tissue. We wanted to know if there was a difference between an optimal immune response that aims to kill cancer and an unwanted response that could affect healthy tissue. Identifying the distinctive elements between these two immune responses allows the development of new, more effective and less toxic therapeutic approaches. Keywords: Cancer; Cells; Tissues, Tumors; Prevention, Prognosis; Diagnosis; Imaging; Screening; Treatment; Management

scholarly journals Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy

Gut ◽  
2018 ◽  
Vol 67 (10) ◽  
pp. 1845-1854 ◽  
Author(s):  
Yue Zhao ◽  
Timothy Wai Ho Shuen ◽  
Tan Boon Toh ◽  
Xue Ying Chan ◽  
Min Liu ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Immune Checkpoint ◽  
Drug Testing ◽  
Checkpoint Inhibitors ◽  
Tumour Microenvironment ◽  
Human Immune System ◽  
Patient Derived Xenograft ◽  
Human Immune ◽  
Human Specific

ObjectiveAs the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing.DesignPatient-derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD-scid Il2rg−/− (NSG) mice. The longitudinal changes of the tumour and immune responses as well as the efficacy of immune checkpoint inhibitors are investigated.ResultsSimilar to the clinical outcomes, the human immune system in our model is educated by the tumour and exhibits exhaustion phenotypes such as a significant declination of leucocyte numbers, upregulation of exhaustion markers and decreased the production of human proinflammatory cytokines. Notably, cytotoxic immune cells decreased more rapidly compared with other cell types. Tumour infiltrated T cells have much higher expression of exhaustion markers and lower cytokine production compared with peripheral T cells. In addition, tumour-associated macrophages and myeloid-derived suppressor cells are found to be highly enriched in the tumour microenvironment. Interestingly, the tumour also changes gene expression profiles in response to immune responses by upregulating immune checkpoint ligands. Most importantly, in contrast to the NSG model, our model demonstrates both therapeutic and side effects of immune checkpoint inhibitors pembrolizumab and ipilimumab.ConclusionsOur work provides a model for immune-oncology study and a useful parallel-to-human platform for anti-HCC drug testing, especially immunotherapy.

scholarly journals Cancer Immunotherapy by Blocking Immune Checkpoints on Innate Lymphocytes

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3504
Author(s):  
Silvia Pesce ◽  
Sara Trabanelli ◽  
Clara Di Vito ◽  
Marco Greppi ◽  
Valentina Obino ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Checkpoint ◽  
Nk Cell ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Lymphoid Cells ◽  
Immune Checkpoints ◽  
Tissue Damages ◽  
Innate Lymphocytes

Immune checkpoints refer to a plethora of inhibitory pathways of the immune system that play a crucial role in maintaining self-tolerance and in tuning the duration and amplitude of physiological immune responses to minimize collateral tissue damages. The breakdown of this delicate balance leads to pathological conditions, including cancer. Indeed, tumor cells can develop multiple mechanisms to escape from immune system defense, including the activation of immune checkpoint pathways. The development of monoclonal antibodies, targeting inhibitory immune checkpoints, has provided an immense breakthrough in cancer therapy. Immune checkpoint inhibitors (ICI), initially developed to reverse functional exhaustion in T cells, recently emerged as important actors in natural killer (NK)-cell-based immunotherapy. Moreover, the discovery that also helper innate lymphoid cells (ILCs) express inhibitory immune checkpoints, suggests that these molecules might be targeted on ILCs, to modulate their functions in the tumor microenvironment. Recently, other strategies to achieve immune checkpoint blockade have been developed, including miRNA exploiting systems. Herein, we provide an overview of the current knowledge on inhibitory immune checkpoints on NK cells and ILCs and we discuss how to target these innate lymphocytes by ICI in both solid tumors and hematological malignancies.

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