Expression of TAM-R in Human Immune Cells and Unique Regulatory Function of MerTK in IL-10 Production by Tolerogenic DC

BackgroundStimulator of Interferon Genes (STING) is a major player in the activation of robust innate immune response leading to initiation and enhancement of tumor-specific adaptive immunity. Several clinical and pre-clinical programs have shown that activation of the STING pathway triggers immune-mediated antitumor response. Although vast majority of programs focus on development of analogues of the endogenous STING ligands, their chemical nature and stability often limit their use to local administration. Herein, we present recent results from the development of our selective non-nucleotide, non-macrocyclic, small molecule direct STING agonists, suitable for systemic administration, characterized by improved activity in human immune cells.MethodsBinding to recombinant STING protein was examined using FTS, MST, FP and crystallography studies. Phenotypic screen was performed in THP-1 Dual reporter cells. Mouse bone marrow-derived dendritic cells (BMDC) were obtained from C57BL/6 mice and differentiated with mIL-4 and mGM-CSF. STING agonists were administered into BALB/c mice and cytokine release was measured in plasma. Additionally, mice were inoculated with CT26 murine colon carcinoma or EMT6 murine breast carcinoma cells and the compound was administered, followed by the regular tumor growth and body weight monitoring.ResultsRyvu’s small-molecule agonists demonstrate strong binding affinity to recombinant STING proteins across all tested species. The compounds bind to all human STING protein variants and trigger pro-inflammatory cytokine release from human immune cells regardless of the STING haplotype. Moreover, new generation of developed agonists show significantly improved binding to human protein as well as in vitro activity on human cells. Systemic, intravenous in vivo administration leads to a dose-dependent upregulation of STING-dependent pro-inflammatory cytokines, which results in a dose-dependent antitumor efficacy observed in CT26 and EMT6 mouse cancer models, leading to complete tumor remissions in all treated animals. Furthermore, observed efficacy is accompanied by development of a lasting immunological response demonstrated by lack of tumor engraftment or a delayed tumor growth in cured animals challenged with repeated inoculation of cancer cells.ConclusionsNew generation Ryvu’s STING agonists are strong and selective activators of STING-dependent signaling in both mouse and human immune cells promoting anti-tumor immunity. Treatment with Ryvu’s small-molecule STING agonists leads to engagement of the immune system which results in a complete tumor remission and development of immunological memory of the cancer antigens. The compounds show good selectivity and ADME properties enabling development for systemic administration. In addition developed compounds maintain small functional handles amenable to linker attachment making the series suitable for versatile development as single agents, for combinations with immunotherapies or as targeted agents.

Download Full-text

AB0057 Influence of PVA coated nanoparticles on survival and functionality of human immune cells

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2012-eular.57 ◽

2013 ◽

Vol 71 (Suppl 3) ◽

pp. 640.17-640

Author(s):

C. Strehl ◽

T. Gaber ◽

M. Wagegg ◽

M. Jakstadt ◽

M. Hahne ◽

...

Keyword(s):

Immune Cells ◽

Coated Nanoparticles ◽

Human Immune

Download Full-text

Multi tissue processing for single cell sequencing of human immune cells v1

10.17504/protocols.io.bz4qp8vw ◽

2021 ◽

Author(s):

Daniel Rainbow ◽

Sarah Howlett ◽

Lorna Jarvis ◽

Joanne Jones

Keyword(s):

Single Cell ◽

Rna Sequencing ◽

Immune Cells ◽

Human Tissues ◽

Single Cell Sequencing ◽

Tissue Processing ◽

Simultaneous Processing ◽

Single Cell Rna Sequencing ◽

Human Immune

This protocol has been developed for the simultaneous processing of multiple human tissues to extract immune cells for single cell RNA sequencing using the 10X platform, and ideal for atlasing projects. Included in this protocol are the steps needed to go from tissue to loading the 10X Chromium for single cell RNA sequencing and includes the hashtag and CiteSeq labelling of cells as well as the details needed to stimulate cells with PMA+I.

Download Full-text

New derivatives of xanthenone-4-acetic acid: Synthesis, pharmacological profile and effect on TNF-α and NO production by human immune cells

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2006.02.003 ◽

2006 ◽

Vol 14 (12) ◽

pp. 4101-4109 ◽

Cited By ~ 8

Author(s):

Silvia Gobbi ◽

Federica Belluti ◽

Alessandra Bisi ◽

Lorna Piazzi ◽

Angela Rampa ◽

...

Keyword(s):

Acetic Acid ◽

Immune Cells ◽

Acid Synthesis ◽

No Production ◽

Pharmacological Profile ◽

Tnf Α ◽

Human Immune ◽

Derivatives Of

Download Full-text

Normal human immune cells are sensitive to telomerase inhibition by Brassica -derived 3,3-diindolylmethane,partly mediated via ERα/β-AP1 signaling

Molecular Nutrition & Food Research ◽

10.1002/mnfr.201600524 ◽

2017 ◽

Vol 61 (9) ◽

pp. 1600524 ◽

Cited By ~ 2

Author(s):

Corinna Herz ◽

Hoai Thi Thu Tran ◽

Steffen Landerer ◽

Johanna Gaus ◽

Nina Schlotz ◽

...

Keyword(s):

Immune Cells ◽

Telomerase Inhibition ◽

Normal Human ◽

Human Immune

Download Full-text

Role of NFAT in the Progression of Diabetic Atherosclerosis

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.635172 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yaoyao Cai ◽

Haipeng Yao ◽

Zhen Sun ◽

Ying Wang ◽

Yunyun Zhao ◽

...

Keyword(s):

Transcription Factor ◽

Cardiovascular System ◽

Signaling Pathways ◽

Immune Cells ◽

Target Genes ◽

Vascular System ◽

Foam Cell ◽

Vascular Diseases ◽

Regulatory Function ◽

Foam Cell Formation

Nuclear factor of activated T cells (NFAT) is a transcription factor with a multidirectional regulatory function, that is widely expressed in immune cells, including cells in the cardiovascular system, and non-immune cells. A large number of studies have confirmed that calcineurin/NFAT signal transduction is very important in the development of vascular system and cardiovascular system during embryonic development, and plays some role in the occurrence of vascular diseases such as atherosclerosis, vascular calcification, and hypertension. Recent in vitro and in vivo studies have shown that NFAT proteins and their activation in the nucleus and binding to DNA-related sites can easily ɨnduce the expression of downstream target genes that participate in the proliferation, migration, angiogenesis, and vascular inflammation of vascular wall related cells in various pathophysiological states. NFAT expression is regulated by various signaling pathways, including CD137-CD137L, and OX40-OX40L pathways. As a functionally diverse transcription factor, NFAT interacts with a large number of signaling molecules to modulate intracellular and extracellular signaling pathways. These NFAT-centered signaling pathways play important regulatory roles in the progression of atherosclerosis, such as in vascular smooth muscle cell phenotypic transition and migration, endothelial cell injury, macrophage-derived foam cell formation, and plaque calcification. NFAT and related signaling pathways provide new therapeutic targets for vascular diseases such as atherosclerosis. Hence, further studies of the mechanism of NFAT in the occurrence and evolution of atherosclerosis remain crucial.

Download Full-text