scholarly journals The CC′ loop of IgV domains of the immune checkpoint receptors, plays a key role in receptor:ligand affinity modulation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Shankar V. Kundapura ◽  
Udupi A. Ramagopal
Keyword(s):  
Immune Checkpoint ◽  
Rational Design ◽  
Protein Docking ◽  
Immune Checkpoints ◽  
Negative Regulators ◽  
Durable Response ◽  
Affinity Modulation ◽  
Polar Interactions ◽  
Checkpoint Receptors

AbstractAntibodies targeting negative regulators of immune checkpoints have shown unprecedented and durable response against variety of malignancies. While the concept of blocking the negative regulators of the immune checkpoints using mAbs appears to be an outstanding approach, their limited effect and several drawbacks, calls for the rational design of next generation of therapeutics. Soluble isoforms of the negative regulators of immune checkpoint pathways are expressed naturally and regulate immune responses. This suggests, affinity-modified versions of these self-molecules could be effective lead molecules for immunotherapy. To obtain better insights on the hotspot regions for modification, we have analysed structures of 18 immune receptor:ligand complexes containing the IgV domain. Interestingly, this analysis reveals that the CC′ loop of IgV domain, a loop which is distinct from CDRs of antibodies, plays a pivotal role in affinity modulation, which was previously not highlighted. It is noteworthy that a ~5-residue long CC′ loop in a ~120 residue protein makes significant number of hydrophobic and polar interactions with its cognate ligand. The post-interaction movement of CC′ loop to accommodate the incoming ligands, seems to provide additional affinity to the interactions. In silico replacement of the CC′ loop of TIGIT with that of Nectin-2 and PVR followed by protein docking trials suggests a key role of the CC′ loop in affinity modulation in the TIGIT/Nectin pathway. The CC′ loop appears to be a hotspot for the affinity modification without affecting the specificity to their cognate receptors.

scholarly journals The CC′ loop of IgV domain containing immune checkpoint receptors: From a bystander to an active determinant of receptor:ligand binding

2019 ◽  
Author(s):  
Shankar V. Kundapura ◽  
Udupi A. Ramagopal
Keyword(s):  
Immune Response ◽  
Rational Design ◽  
Immune Checkpoints ◽  
Affinity Modification ◽  
Negative Regulators ◽  
Limited Effect ◽  
Durable Response ◽  
Tumor Penetration ◽  
Affinity Modulation ◽  
Checkpoint Receptors

AbstractAntibodies targeting negative regulators of immune checkpoints have shown unprecedented and durable response against variety of malignancies. While the concept of blocking the negative regulators of immune checkpoints using mAbs appears to be an outstanding approach, their limited effect and several drawbacks such as resistance, poor solid tumor penetration and so on, calls for the rational design of next generation of therapeutics. Soluble isoforms of negative regulators of immune checkpoints are expressed naturally and are shown to regulate the immune response, suggesting the soluble version of these molecules and affinity-modified versions of these self-molecules could be effective lead molecules for immunotherapy. To get a better insight on hotspot regions for modification, we have analysed structures of available immune receptor:ligand complexes containing IgV domains. Interestingly, this analysis reveals that the CC′ loop of IgV domain, a loop which is distinct from CDRs which are generally utilized by antibodies to recognize antigens, plays a pivotal role in affinity modulation. Here, we present several examples of cognate partner specific conformational variation observed in CC′ loop of several checkpoint receptor:ligand complexes. In addition,in silicoswapping of CC′ loop targeting TIGIT:Nectin-2/PVR pathway corroborated well with biophysically determined affinity values for these complexes. Thus, CC′ loop appears to be a hotspot for affinity modification without affecting the specificity to their cognate receptors, an important requirement to avoid unintended interaction of these modified molecules with undesired targets.

scholarly journals Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Yuqing Cao ◽  
Xiaoyu Wang ◽  
Tianqiang Jin ◽  
Yu Tian ◽  
Chaoliu Dai ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Immune Checkpoint ◽  
Therapeutic Target ◽  
Nk Cell ◽  
Lymphoid Cells ◽  
Immune Checkpoints ◽  
Immune Checkpoint Molecules

Abstract Recent studies have demonstrated the potential of natural killer (NK) cells in immunotherapy to treat multiple types of cancer. NK cells are innate lymphoid cells that play essential roles in tumor surveillance and control that efficiently kill the tumor and do not require the major histocompatibility complex. The discovery of the NK’s potential as a promising therapeutic target for cancer is a relief to oncologists as they face the challenge of increased chemo-resistant cancers. NK cells show great potential against solid and hematologic tumors and have progressively shown promise as a therapeutic target for cancer immunotherapy. The effector role of these cells is reliant on the balance of inhibitory and activating signals. Understanding the role of various immune checkpoint molecules in the exhaustion and impairment of NK cells when their inhibitory receptors are excessively expressed is particularly important in cancer immunotherapy studies and clinical implementation. Emerging immune checkpoint receptors and molecules have been found to mediate NK cell dysfunction in the tumor microenvironment; this has brought up the need to explore further additional NK cell-related immune checkpoints that may be exploited to enhance the immune response to refractory cancers. Accordingly, this review will focus on the recent findings concerning the roles of immune checkpoint molecules and receptors in the regulation of NK cell function, as well as their potential application in tumor immunotherapy.

scholarly journals The Role of Chemokines in Cervical Cancers

Medicina ◽  
2021 ◽  
Vol 57 (11) ◽  
pp. 1141
Author(s):  
Fabian Garrido ◽  
Carl Mathis Wild ◽  
Johanna Mittelberger ◽  
Franziska Dobler ◽  
Mariella Schneider ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Immune Checkpoint ◽  
Cervical Dysplasia ◽  
Experimental Studies ◽  
Immune Checkpoints ◽  
Clear Understanding ◽  
Cervical Cancers ◽  
Therapy Development

Both clinical-pathological and experimental studies have shown that chemokines play a key role in activating the immune checkpoint modulator in cervical cancer progression and are associated with prognosis in tumor cell proliferation, invasion, angiogenesis, chemoresistance, and immunosuppression. Therefore, a clear understanding of chemokines and immune checkpoint modulators is essential for the treatment of this disease. This review discusses the origins and categories of chemokines and the mechanisms that are responsible for activating immune checkpoints in cervical dysplasia and cancer, chemokines as biomarkers, and therapy development that targets immune checkpoints in cervical cancer research.

scholarly journals Novel mechanism in cardiac injury: immune checkpoints

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E.M Screever ◽  
M.L Axelrod ◽  
M.A Blair ◽  
D.Z Trykall ◽  
J.V Barnett ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Troponin I ◽  
Immune Cell ◽  
Cardiac Injury ◽  
Cell Infiltration ◽  
Immune Checkpoints ◽  
Funding Source ◽  
Immune Cell Infiltration ◽  
Isolated Cardiomyocytes

Abstract Background Immune checkpoint inhibitors (ICI), specifically directed against CTLA-4 and PD-1, have revolutionized cancer therapy but are associated with immune-related adverse events, including fulminant myocarditis. The mechanisms are unknown, but one possibility is that CTLA-4 and PD-1 play a critical role in cardiovascular homeostasis. Purpose The purpose of this study is to investigate the role of these immune checkpoints in cardiac injury. We hypothesize that cardiomyocytes can express immune checkpoint ligands in response to stress and that CTLA-4 and/or PD-1 play a key role in cardiac response to injury. Methods We measured expression levels of CTLA-4 ligands (Cd80, Cd86) and PD-1 ligands (Pdcdl1, Pdcdl2) in in vitro and in vivo models of cardiac injury, including iPSC-derived cardiomyocytes (iPSC-CM) and diseased human cardiac samples. Immunofluorescent staining and multiplex immunohistochemistry were used to derive more granular data on cell type expressing specific immune checkpoint associated proteins. To determine the functional role of CTLA-4 and PD-1 in cardiac injury, myocardial infarction (MI) was induced in C57Bl/6 mice treated with anti-CTLA-4 or in mice with a genetic knock-out of CTLA-4 and PD-1 (Pdcd1−/−Ctla4+/+ and Pdcd1−/−Ctla4+/−). Flow cytometry was performed 2-days post-MI to determine immune cell infiltration, echocardiography was performed 7-days and 28-days post-MI and plasma samples were analyzed for ANP and Troponin I. Results Doxorubicin or hypoxia increased expression of Cd80, Cd86, Pdcdl1 and Pdcdl2 in iPSC-CM. After MI, isolated cardiomyocytes from the ischemic/border zone area yielded significant increased expression of both Cd80 and Cd86, which was confirmed at the protein level. However, pharmacologic inhibition of CTLA-4 during MI resulted in better survival compared to no treatment (p<0.007). No differences were seen in immune cell infiltration, troponin I and ANP levels and echocardiography. Pdcd1−/-Ctla4+/+ and Pdcd1−/−Ctla4+/− mice showed a decrease in immune cell infiltration. Conclusions Whole hearts, isolated cardiomyocytes and iPSC-CM from both mice and humans express immune checkpoint ligands in response to cardiac injury. Pharmacologic or genetic inhibition of CTLA-4 and PD-1 in MI did not result in adverse effects regarding survival, cardiac function, immune cell infiltration and heart enzyme levels in mice. These data support the hypothesis that immune checkpoint pathways play a role in cardiac injury and in these preliminary studies immune checkpoint inhibition during cardiac ischemic injury did not result in adverse effects. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health grants R56 HL141466 and R01 HL141466

scholarly journals Molecular Scale Spatio-Chemical Control of the Activating-Inhibitory Signal Integration in NK Cells

2020 ◽  
Author(s):  
Esti Toledo ◽  
Guillaume Le Saux ◽  
Long Li ◽  
Maor Rosenberg ◽  
Yossi Keidar ◽  
...  
Keyword(s):  
Nk Cells ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Spatial Interaction ◽  
Immune Checkpoints ◽  
Cytotoxic Lymphocytes ◽  
Inhibitory Receptors ◽  
Molecular Scale ◽  
Cell Niche

AbstractThe role of the spatial juxtaposition between activating and inhibitory receptors in cytotoxic lymphocytes has been strongly debated in the context of the inhibition of immune signaling. The challenge in addressing this problem was so far a lack of experimental tools which can simultaneously manipulate different signaling molecules. Here, we circumvent this challenge by introducing a nanoengineered multifunctional cell niche, in which activating and inhibitory ligands are positioned with molecular-scale variability and control, and applied it to elucidate the role of the spatial juxtaposition between ligands for NKG2D and KIR2DL1 – activating and inhibitory receptors in Natural Killer (NK) cells – in KIR2DL1-mediated inhibition of NKG2D signaling. We realized the niche by a nanopatterning of nanodots of different metals with molecular scale registry in one lithographic step, followed by a novel ternary functionalization of the fabricated bi-metallic pattern and its background to with three distinct biochemical moieties. We found, that within the probed range, the 40 nm gap between the activating and inhibitory ligands provided an optimal inhibition condition. Supported by theoretical modeling and simulations we interpret these findings as a consequence of the size and conformational flexibility of the ligands in their spatial interaction. Our findings provide an important insight onto the spatial mechanism of the inhibitory immune checkpoints, whose understanding is both fundamentally important, and essential for the rational design of future immunotherapies. Furthermore, our approach is highly versatile and paves the way to numerous complex molecular platforms aimed at revealing molecular mechanisms through which receptors integrate their signals.

scholarly journals Current Progress and Future Perspectives of Immune Checkpoint in Cancer and Infectious Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Cai ◽  
Huajie Zhan ◽  
Yuguang Ye ◽  
Jinjin Yang ◽  
Minghui Zhang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Immune Checkpoint ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Microbial Infection ◽  
Antiviral Immune Response

The inhibitory regulators, known as immune checkpoints, prevent overreaction of the immune system, avoid normal tissue damage, and maintain immune homeostasis during the antimicrobial or antiviral immune response. Unfortunately, cancer cells can mimic the ligands of immune checkpoints to evade immune surveillance. Application of immune checkpoint blockade can help dampen the ligands expressed on cancer cells, reverse the exhaustion status of effector T cells, and reinvigorate the antitumor function. Here, we briefly introduce the structure, expression, signaling pathway, and targeted drugs of several inhibitory immune checkpoints (PD-1/PD-L1, CTLA-4, TIM-3, LAG-3, VISTA, and IDO1). And we summarize the application of immune checkpoint inhibitors in tumors, such as single agent and combination therapy and adverse reactions. At the same time, we further discussed the correlation between immune checkpoints and microorganisms and the role of immune checkpoints in microbial-infection diseases. This review focused on the current knowledge about the role of the immune checkpoints will help in applying immune checkpoints for clinical therapy of cancer and other diseases.

scholarly journals The Role of Immunotherapy in the Treatment of Adrenocortical Carcinoma

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 98
Author(s):  
Izabela Karwacka ◽  
Łukasz Obołończyk ◽  
Sonia Kaniuka-Jakubowska ◽  
Krzysztof Sworczak
Keyword(s):  
Immune Checkpoint ◽  
Adrenocortical Carcinoma ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Acquired Resistance ◽  
Distant Metastases ◽  
Immune Checkpoints ◽  
High Tendency

Adrenocortical carcinoma (ACC) is a rare epithelial neoplasm, with a high tendency for local invasion and distant metastases, with limited treatment options. Surgical treatment is the method of choice. For decades, the mainstay of pharmacological treatment has been the adrenolytic drug mitotane, in combination with chemotherapy. Immunotherapy is the latest revolution in cancer therapy, however preliminary data with single immune checkpoint inhibitors showed a modest activity in ACC patients. The anti-neoplastic activity of immune checkpoint inhibitors such as anti-cytotoxic-T-lymphocyte-associated-antigen 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), and anti-PD-ligand-1 (PD-L1) antibodies in different solid tumors has aroused interest to explore the potential therapeutic effect in ACC as well. Multiple ongoing clinical trials are currently evaluating the role of immune checkpoint inhibitors in ACC (pembrolizumab, combination pembrolizumab and relacorilant, nivolumab, combination nivolumab and ipilimumab). The primary and acquired resistance to immunotherapy continue to counter treatment efficacy. Therefore, attempts are made to combine therapy: anti-PD-1 antibody and anti-CTLA-4 antibody, anti-PD-1 antibody and antagonist of the glucocorticoid receptor. The inhibitors of immune checkpoints would benefit patients with antitumor immunity activated by radiotherapy. Immunotherapy is well tolerated by patients; the most frequently observed side effects are mild. The most common adverse effects of immunotherapy are skin and gastrointestinal disorders. The most common endocrinopathy during anti-CTLA treatment is pituitary inflammation and thyroid disorders.

scholarly journals Immune Checkpoints: Novel Therapeutic Targets to Attenuate Sepsis-Induced Immunosuppression

2021 ◽  
Vol 11 ◽  
Author(s):  
Margaret A. McBride ◽  
Tazeen K. Patil ◽  
Julia K. Bohannon ◽  
Antonio Hernandez ◽  
Edward R. Sherwood ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Clinical Studies ◽  
Immune Checkpoints ◽  
Specific Cell ◽  
Blood Leukocytes ◽  
Antibiotic Resistant ◽  
Definitive Therapy ◽  
Rising Incidence ◽  
Checkpoint Receptors ◽  
Inhibitory Immune Checkpoint

Sepsis is a leading cause of death in intensive care units and survivors develop prolonged immunosuppression and a high incidence of recurrent infections. No definitive therapy exists to treat sepsis and physicians rely on supportive care including antibiotics, intravenous fluids, and vasopressors. With the rising incidence of antibiotic resistant microbes, it is becoming increasingly critical to discover novel therapeutics. Sepsis-induced leukocyte dysfunction and immunosuppression is recognized as an important contributor towards increased morbidity and mortality. Pre-clinical and clinical studies show that specific cell surface inhibitory immune checkpoint receptors and ligands including PD-1, PD-L1, CTLA4, BTLA, TIM3, OX40, and 2B4 play important roles in the pathophysiology of sepsis by mediating a fine balance between host immune competency and immunosuppression. Pre-clinical studies targeting the inhibitory effects of these immune checkpoints have demonstrated reversal of leukocyte dysfunction and improved host resistance of infection. Measurement of immune checkpoint expression on peripheral blood leukocytes may serve as a means of stratifying patients to direct individualized therapy. This review focuses on advances in our understanding of the role of immune checkpoints in the host response to infections, and the potential clinical application of therapeutics targeting the inhibitory immune checkpoint pathways for the management of septic patients.

scholarly journals Immune Checkpoints in Viral Infections

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 1051
Author(s):  
Huiming Cai ◽  
Ge Liu ◽  
Jianfeng Zhong ◽  
Kai Zheng ◽  
Haitao Xiao ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Cancer Cells ◽  
Antiviral Therapy ◽  
Immune Checkpoint ◽  
Viral Infections ◽  
Immune Checkpoints ◽  
Chronic Viral Infections ◽  
Infected Cells

As evidence has mounted that virus-infected cells, such as cancer cells, negatively regulate the function of T-cells via immune checkpoints, it has become increasingly clear that viral infections similarly exploit immune checkpoints as an immune system escape mechanism. Although immune checkpoint therapy has been successfully used in cancer treatment, numerous studies have suggested that such therapy may also be highly relevant for treating viral infection, especially chronic viral infections. However, it has not yet been applied in this manner. Here, we reviewed recent findings regarding immune checkpoints in viral infections, including COVID-19, and discussed the role of immune checkpoints in different viral infections, as well as the potential for applying immune checkpoint blockades as antiviral therapy.

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