scholarly journals 16 Tumor growth inhibition mediated by a single dose of intratumoral TransCon™ TLR7/8 agonist was associated with activated circulating T and B cells and sustained low levels of systemic cytokines

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A18-A18
Author(s):  
Amer Mirza ◽  
Luis Zuniga ◽  
Karan Uppal ◽  
Kathy Bang ◽  
Enping Hong ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Innate Immune ◽  
Tumor Growth Inhibition ◽  
Innate Immune Cells ◽  
Tlr Agonists ◽  
Adaptive Immune ◽  
Cytokines And Chemokines ◽  
Anti Tumor Activity

BackgroundTLR agonists can elicit anti-tumor activity by activating innate immune cells and promoting a proinflammatory microenvironment. Local delivery of TLR agonists has shown encouraging preclinical and clinical anti-tumor activity. However, intratumoral (IT) delivery of naked TLR agonists such as resiquimod, a TLR7/8 agonist, can lead to rapid efflux from the tumor, resulting in acute high systemic drug exposure and transient but high level of peripheral proinflammatory cytokines, thus limiting anti-tumor benefit and increasing risk of cytokine-driven adverse effects.MethodsTransCon™ TLR7/8 Agonist was designed to elicit a sustained and local release of resiquimod following IT administration of a hydrogel depot. In the syngeneic murine CT26 tumor model, a single IT injection of TransCon TLR7/8 Agonist monotherapy was sufficient to induce potent tumor growth inhibition. Following treatment, the induction of key cytokines and chemokines associated with innate immunity was determined.ResultsProinflammatory cytokines (IL-1b, IL-6, and TNFα) were induced following IT TransCon TLR7/8 Agonist treatment, but in contrast to free resiquimod, peak levels were more than 10-fold lower than those observed with an equimolar dose of free resiquimod. The circulating levels of these cytokines were sustained above control alone through Day 21. TH1-associated IFNγ was induced with levels increased at Day 1 and maintained at Day 7. Additionally, expression of myeloid-associated chemokines (KC/GROa/CXCL1, MCP-1/CCL2, IP-10/CXCL10, and MIP-1a/CCL3) were induced and sustained in a largely dose-dependent manner through Day 21. The sustained increase in cytokines was consistent with an increase in circulating innate immune cells, such as NK and myeloid cells. Furthermore, evidence of adaptive immune cell activation was observed as indicated by expression of Ly6C, ICOS and Ki67, which were increased on CD8+ T cells, CD4+ T cells (Ki67, ICOS), and B cells (Ly6C).ConclusionsThese data show that a single IT injection of TransCon TLR7/8 Agonist can elicit sustained expression of key cytokines and chemokines, promote innate immune cell mobilization, activate adaptive immune cells, and mediate robust anti-tumor activity. The levels of the cytokines remained relatively low through the observation period of 21 days, suggesting a low risk of systemic cytokine-associated adverse events. The increase in activated B, T, and NK cells in blood was associated with induction of a potent anti-tumor response, further supporting TransCon TLR7/8 Agonist as a novel and potentially efficacious PRRA therapy. A clinical trial to evaluate its safety and efficacy in cancer patients is currently underway (transcendIT-101; NCT04799054).Ethics ApprovalThe animal studies described were performed in accordance with the ‘Guide for the Care and Use of Laboratory Animals: Eighth Edition’ and approved by the institutional animal care and use committee (IACUC).

scholarly journals IFN-γPriming Effects on the Maintenance of Effector Memory CD4+T Cells and on Phagocyte Function: Evidences from Infectious Diseases

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Henrique Borges da Silva ◽  
Raíssa Fonseca ◽  
José M. Alvarez ◽  
Maria Regina D’Império Lima
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Innate Immune ◽  
Effector Memory ◽  
Innate Immune Cells ◽  
Chronic Infections ◽  
Cell Functions ◽  
Memory Cd4 T Cells

Although it has been established that effector memory CD4+T cells play an important role in the protective immunity against chronic infections, little is known about the exact mechanisms responsible for their functioning and maintenance, as well as their effects on innate immune cells. Here we review recent data on the role of IFN-γpriming as a mechanism affecting both innate immune cells and effector memory CD4+T cells. Suboptimal concentrations of IFN-γare seemingly crucial for the optimization of innate immune cell functions (including phagocytosis and destruction of reminiscent pathogens), as well as for the survival and functioning of effector memory CD4+T cells. Thus, IFN-γpriming can thus be considered an important bridge between innate and adaptive immunity.

scholarly journals Innate Immune Cells in Pressure Overload-Induced Cardiac Hypertrophy and Remodeling

2021 ◽  
Vol 9 ◽  
Author(s):  
Xin Liu ◽  
Guo-Ping Shi ◽  
Junli Guo
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mast Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Pressure Overload ◽  
Natural Killer T Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Killer T Cells

Pressure overload and heart failure are among the leading causes of cardiovascular morbidity and mortality. Accumulating evidence suggests that inflammatory cell activation and release of inflammatory mediators are of vital importance during the pathogenesis of these cardiac diseases. Yet, the roles of innate immune cells and subsequent inflammatory events in these processes remain poorly understood. Here, we outline the possible underlying mechanisms of innate immune cell participation, including mast cells, macrophages, monocytes, neutrophils, dendritic cells, eosinophils, and natural killer T cells in these pathological processes. Although these cells accumulate in the atrium or ventricles at different time points after pressure overload, their cardioprotective or cardiodestructive activities differ from each other. Among them, mast cells, neutrophils, and dendritic cells exert detrimental function in experimental models, whereas eosinophils and natural killer T cells display cardioprotective activities. Depending on their subsets, macrophages and monocytes may exacerbate cardiodysfunction or negatively regulate cardiac hypertrophy and remodeling. Pressure overload stimulates the secretion of cytokines, chemokines, and growth factors from innate immune cells and even resident cardiomyocytes that together assist innate immune cell infiltration into injured heart. These infiltrates are involved in pro-hypertrophic events and cardiac fibroblast activation. Immune regulation of cardiac innate immune cells becomes a promising therapeutic approach in experimental cardiac disease treatment, highlighting the significance of their clinical evaluation in humans.

scholarly journals Innate Immunity Mediated Inflammation and Beta Cell Function: Neighbors or Enemies?

2021 ◽  
Vol 11 ◽  
Author(s):  
Antonio Citro ◽  
Francesco Campo ◽  
Erica Dugnani ◽  
Lorenzo Piemonti
Keyword(s):  
T Cells ◽  
Beta Cell ◽  
Immune Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Active Role ◽  
Pancreatic Tissue ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Beta Cell Destruction

Type 1 diabetes (T1D) is still considered a huge burden because the available treatments are not effective in preventing the onset or progression of the disease. Recently, the idea that diabetes is an autoimmune disease mediated exclusively by T cells has been reshaped. In fact, T cells are not the only players with an active role in beta cell destruction. Macrophages and neutrophils, which physiologically reside in pancreatic tissue, can also participate in tissue homeostasis and damage by promoting innate immune responses and modulating inflammation. During the development of the pancreatic islet inflammation there is a strong interplay of both adaptive and innate immune cells, and the presence of innate immune cells has been demonstrated both in exocrine and endocrine pancreatic compartments during the earliest stages of insulitis. Innate immune cell populations secrete cytokines, which must be considered both as physiological and pathological mediators. In fact, it has been demonstrated that cytokines could regulate directly and indirectly insulin secretion and, simultaneously, trigger inflammatory reaction. Indeed, cytokines pathways could represent targets both to improve glucose metabolism and to prevent autoimmune damage. Concordantly, the combination of immunomodulatory strategies against both innate and adaptive immunity should be tested in the next future, as they can be more efficient to prevent or delay islet damage and T1D onset.

scholarly journals Profiles of Transforming Activations of Immune Cells as Infiltrative Dimensions in Definition of TCD4+ helper Cells in Neuroinflammation of Multiple Sclerosis Type

2020 ◽  
Vol 2 (2) ◽  
pp. 1-4
Author(s):  
Lawrence M Agius ◽  
Keyword(s):  
Immune Cells ◽  
Innate Immune ◽  
Environmental Cues ◽  
Innate Immune Cells ◽  
Adaptive Immune ◽  
Cytokines And Chemokines ◽  
Adaptive Immune Cells ◽  
Definition Of ◽  
Molecular Patterns ◽  
Reactive Lymphocytes

Processes of induced generation of auto-reactive lymphocytes are direct consequential formulas in defining profiles of activation and re-activation of immune cells both peripherally and in CNS parenchyma. Such profiles of ongoing transformation include in particular the dimensional reconstitution of both Th1 and Th17 CD4+ lymphocytes within the CNS parenchyma. The dynamics of infiltration and preceding extravasation of immunecompetent cells allows a permissive environment for the actions of cytokines and chemokines in terms specific for the dynamics of stimulated secretion by innate immune cells and of adaptive immune cells. Such integration is defining term of conditioning of permissive micro environmental cues in pathogen-recognition and molecular patterns of recognition of various agonists including bacteria and viruses.

scholarly journals Innate Immune Cells and Their Contribution to T-Cell-Based Immunotherapy

2020 ◽  
Vol 21 (12) ◽  
pp. 4441 ◽  
Author(s):  
Pierpaolo Ginefra ◽  
Girieca Lorusso ◽  
Nicola Vannini
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
Immune Cells ◽  
Adoptive Cell Therapy ◽  
Adaptive Immune Response ◽  
Immune Checkpoint Blockade ◽  
Innate Immune ◽  
Innate Immune Cells

In recent years, immunotherapy has become the most promising therapy for a variety of cancer types. The development of immune checkpoint blockade (ICB) therapies, the adoptive transfer of tumor-specific T cells (adoptive cell therapy (ACT)) or the generation of T cells engineered with chimeric antigen receptors (CAR) have been successfully applied to elicit durable immunological responses in cancer patients. However, not all the patients respond to these therapies, leaving a consistent gap of therapeutic improvement that still needs to be filled. The innate immune components of the tumor microenvironment play a pivotal role in the activation and modulation of the adaptive immune response against the tumor. Indeed, several efforts are made to develop strategies aimed to harness innate immune cells in the context of cancer immunotherapy. In this review, we describe the contribution of innate immune cells in T-cell-based cancer immunotherapy and the therapeutic approaches implemented to broaden the efficacy of these therapies in cancer patients.

scholarly journals Pannexin-1 Channels as Mediators of Neuroinflammation

2021 ◽  
Vol 22 (10) ◽  
pp. 5189
Author(s):  
Joon Ho Seo ◽  
Miloni S. Dalal ◽  
Jorge E. Contreras
Keyword(s):  
Immune Cells ◽  
Neurological Diseases ◽  
Atp Release ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Damage Site ◽  
Pannexin 1 ◽  
Cytokines And Chemokines ◽  
Secondary Damage ◽  
Dying Cells

Neuroinflammation is a major component of central nervous system (CNS) injuries and neurological diseases, including Alzheimer’s disease, multiple sclerosis, neuropathic pain, and brain trauma. The activation of innate immune cells at the damage site causes the release of pro-inflammatory cytokines and chemokines, which alter the functionality of nearby tissues and might mediate the recruitment of leukocytes to the injury site. If this process persists or is exacerbated, it prevents the adequate resolution of the inflammation, and ultimately enhances secondary damage. Adenosine 5′ triphosphate (ATP) is among the molecules released that trigger an inflammatory response, and it serves as a chemotactic and endogenous danger signal. Extracellular ATP activates multiple purinergic receptors (P2X and P2Y) that have been shown to promote neuroinflammation in a variety of CNS diseases. Recent studies have shown that Pannexin-1 (Panx1) channels are the principal conduits of ATP release from dying cells and innate immune cells in the brain. Herein, we review the emerging evidence that directly implicates Panx-1 channels in the neuroinflammatory response in the CNS.

scholarly journals 769 A single dose of intratumoral TransCon™ TLR7/8 agonist monotherapy promoted sustained activation of antigen presenting cells resulting in CD4+ and CD8+ T cell activation and tumor growth inhibition

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A804-A804
Author(s):  
Luis Zuniga ◽  
Karan Uppal ◽  
Kathy Bang ◽  
Enping Hong ◽  
Simran Sabharwal ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Antigen ◽  
Tumor Growth Inhibition ◽  
Tlr Agonists ◽  
Syngeneic Mouse ◽  
Antigen Presenting ◽  
Anti Tumor Activity ◽  
Dose Dependent

BackgroundThe use of pattern recognition receptor agonists (PRRAs) such as Toll-like receptor (TLR) agonists is an attractive approach for cancer immunotherapy. TLR agonism elicits anti-tumor activity by activating antigen presenting cells (APCs) to promote a proinflammatory microenvironment and anti-tumor immunity. Local delivery of TLR agonists has shown encouraging preclinical and clinical anti-tumor benefit. However, intratumoral (IT) delivery of naked PRRAs may lead to rapid effusion from the tumor microenvironment, potentially impacting their effectiveness in inducing local inflammation and may promote systemic cytokine release, increasing the risk of adverse effects.MethodsTransConTM TLR7/8 Agonist was designed to address the current limitations of PRRA therapies and IT delivery through sustained and controlled release of resiquimod, a potent TLR7/8 agonist, following IT administration of a hydrogel depot.ResultsA single IT injection of TransCon TLR7/8 Agonist induced potent tumor growth inhibition in a dose-dependent manner in syngeneic mouse CT26 tumors. Following IT TransCon TLR7/8 Agonist treatment, acute and sustained upregulation of cell surface markers indicative of activation of APCs, such as CD54, CD69, and CD86, in the tumor was observed by fluorescence activated flow cytometry (FACs). Additionally, TransCon TLR7/8 Agonist treatment was associated with an increase in the frequency of APCs with an activated phenotype in tumor draining lymph nodes (LNs). Further, a concomitant potentiation in the frequency of activated CD4 and CD8 T cells in tumor draining LNs following IT TransCon TLR7/8 Agonist treatment was observed, as demonstrated by increased expression of Ki67, ICOS, or granzyme B.ConclusionsThese data support that a single IT dose of TransCon TLR7/8 Agonist can mediate robust anti-tumor activity as a monotherapy in the CT26 syngeneic mouse tumor model while promoting local activation of intratumoral APCs. Such activation may promote tumor antigen uptake and migration to tumor-associated lymphoid tissue, as evidenced by an increase in APCs with an activated phenotype in tumor draining LNs following TransCon TLR7/8 Agonist treatment. Activated tumor antigen-bearing APCs can promote the priming and activation of tumor-specific T cells in the tumor-draining LNs. Consistently, a dose-dependent increase in the frequency of T cells with an activated effector phenotype in tumor draining LNs following administration of TransCon TLR7/8 Agonist was observed. These preclinical data further support TransCon TLR7/8 Agonist as a novel and potentially efficacious PRRA therapy. A clinical trial to evaluate safety and efficacy of TransCon TLR7/8 Agonist as monotherapy, and in combination with pembrolizumab, in cancer patients has been initiated (transcendIT-101; NCT04799054).Ethics ApprovalThe animal studies performed described were performed in accordance with the “Guide for the Care and Use of Laboratory Animals: Eighth Edition” and approved by the institutional animal care and use committee (IACUC).

scholarly journals Adipocytes, Innate Immunity and Obesity: A Mini-Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Alecia M. Blaszczak ◽  
Anahita Jalilvand ◽  
Willa A. Hsueh
Keyword(s):  
Adipose Tissue ◽  
Immune System ◽  
Immune Cells ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Lymphoid Cells ◽  
Innate Immune Cells ◽  
Adaptive Immune

The role of adipose tissue (AT) inflammation in obesity and its multiple related-complications is a rapidly expanding area of scientific interest. Within the last 30 years, the role of the adipocyte as an endocrine and immunologic cell has been progressively established. Like the macrophage, the adipocyte is capable of linking the innate and adaptive immune system through the secretion of adipokines and cytokines; exosome release of lipids, hormones, and microRNAs; and contact interaction with other immune cells. Key innate immune cells in AT include adipocytes, macrophages, neutrophils, and innate lymphoid cells type 2 (ILC2s). The role of the innate immune system in promoting adipose tissue inflammation in obesity will be highlighted in this review. T cells and B cells also play important roles in contributing to AT inflammation and are discussed in this series in the chapter on adaptive immunity.

scholarly journals Adaptive and Innate Immune Cells in Fetal Human Cytomegalovirus-Infected Brains

2020 ◽  
Vol 8 (2) ◽  
pp. 176 ◽  
Author(s):  
Yann Sellier ◽  
Florence Marliot ◽  
Bettina Bessières ◽  
Julien Stirnemann ◽  
Ferechte Encha-Razavi ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Immune Cells ◽  
Plasma Cells ◽  
Ex Vivo ◽  
Fetal Brain ◽  
Brain Lesions ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Infected Cells

Background: The understanding of the pathogenesis of cytomegalovirus (CMV)-induced fetal brain lesions is limited. We aimed to quantify adaptive and innate immune cells and CMV-infected cells in fetal brains with various degrees of brain damage. Methods: In total, 26 archived embedded fetal brains were studied, of which 21 were CMV-infected and classified in severely affected (n = 13) and moderately affected (n = 8), and 5 were uninfected controls. The respective magnitude of infected cells, immune cells (CD8+, B cells, plasma cells, NK cells, and macrophages), and expression of immune checkpoint receptors (PD-1/PD-L1 and LAG-3) were measured by immunochemistry and quantified by quantitative imaging analysis. Results: Quantities of CD8+, plasma cells, NK cells, macrophages, and HCMV+ cells and expression of PD-1/PD-L1 and LAG-3 were significantly higher in severely affected than in moderately affected brains (all p values < 0.05). A strong link between higher number of stained cells for HCMV/CD8 and PD-1 and severity of brain lesions was found by component analysis. Conclusions: The higher expression of CD8, PD-1, and LAG-3 in severely affected brains could reflect immune exhaustion of cerebral T cells. These exhausted T cells could be ineffective in controlling viral multiplication itself, leading to more severe brain lesions. The study of the functionality of brain leucocytes ex vivo is needed to confirm this hypothesis.

scholarly journals Natural Killer Dendritic Cells Enhance Immune Responses Elicited byα-Galactosylceramide-Stimulated Natural Killer T Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-18 ◽  
Author(s):  
Sung Won Lee ◽  
Hyun Jung Park ◽  
Nayoung Kim ◽  
Seokmann Hong
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Natural Killer ◽  
Immune Cells ◽  
Tumor Antigens ◽  
Nkt Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Natural Killer T

Natural killer dendritic cells (NKDCs) possess potent anti-tumor activity, but the cellular effect of NKDC interactions with other innate immune cells is unclear. In this study, we demonstrate that the interaction of NKDCs and natural killer T (NKT) cells is required for the anti-tumor immune responses that are elicited byα-galactosylceramide (α-GC) in mice. The rapid and strong expression of interferon-γby NKDCs afterα-GC stimulation was dependent on NKT cells. Various NK and DC molecular markers and cytotoxic molecules were up-regulated followingα-GC administration. This up-regulation could improve NKDC presentation of tumor antigens and increase cytotoxicity against tumor cells. NKDCs were required for the stimulation of DCs, NK cells, and NKT cells. The strong anti-tumor immune responses elicited byα-GC may be due to the down-regulation of regulatory T cells. Furthermore, the depletion of NKDCs dampened the tumor clearance mediated byα-GC-stimulated NKT cellsin vivo. Taken together, these results indicate that complex interactions of innate immune cells might be required to achieve optimal anti-tumor immune responses during the early stages of tumorigenesis.

Sign in / Sign up

Export Citation Format

Share Document