Biology subjects

Dik, W. A.

Publications and source records attributed to Dik, W. A..

3 recordsLinked to original sources

bioRxiv2025

Adoptive cell therapy using T cell receptors equipped with ICOS yields durable anti-tumor response

Treatment with adoptively transferred T cells is challenged by limited longevity of therapeutic cells within tumors. To enhance the durability of anti-tumor T cell products, we have created T cell receptors (TCRs) with built-in co-stimulatory molecules. We observed that TCRs coupled to ICOS mediated exceptionally long-term responses including delay of tumor recurrence and cures in a mouse tumor model. TCR:ICOS T cells showed enhanced and antigen-specific production of inflammatory cytokines and resistance to exhaustion. Genetic ablation of ICOS-mediated activation of the PI3K-NF{kappa}B pathway neutralized the long-term anti-tumor effects. To translate TCR:ICOS to human T cells, we identified a single amino acid change in the cytosolic tail which was necessary for functional surface expression. Notably, the optimized receptor sustained performance of human T cells upon repeated stimulation across multiple antigen specificities. Collectively, we present a novel and uniformly applicable TCR:ICOS format that supports fitter T cell products for adoptive cell therapy. HighlightsNewly designed co-stimulatory TCR, with extracellular TCR-V and C domains coupled to CD28 transmembrane domain, and ICOS and CD3{varepsilon} intracellular domains (in short TCR:ICOS) provides:[tpltrtarr] durable anti-tumor response and T cell persistence in mouse model [tpltrtarr]inflammatory T cell phenotype and resistance to T cell exhaustion [tpltrtarr]effects via PI3K and NF{kappa}B activation [tpltrtarr]translation to human T cells upon single amino acid mutation in TCR:ICOS tail [tpltrtarr]extension to multiple clinically relevant TCRs while preserving prolonged T cell fitness O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/682056v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1ff752borg.highwire.dtl.DTLVardef@6579d9org.highwire.dtl.DTLVardef@22bdc4org.highwire.dtl.DTLVardef@d8c445_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Differentially polarized macrophages show diverse proangiogenic characteristics under normo- and hyperglycemic conditions

PurposeAngiogenesis is a vital process involved in the formation of new blood vessels from existing ones. Macrophages play a crucial role in initiating endothelial activation and inflammation, and are involved in the pathological angiogenesis. Traditionally, macrophages have been classified, with the pro-angiogenic activity attributed to the M2 phenotype. However, recent evidence challenges the notion that only M2 macrophages possess pro-angiogenic properties. This study aims to investigate the pro- and anti-angiogenic properties of human polarized macrophages in normo- and hyper-glycemic conditions, in order to gain a better insight into the angiogenic capacity of M1- and M2-like macrophages in diabetes. MethodsA comprehensive bioinformatic analysis of pro- and anti-angiogenic gene expression profiles related in M1-vs. M2-polarized macrophages was performed based on a large previously published dataset. The most contributing differentially expressed genes in angiogenesis were selected for further validation. Macrophages were generated and polarized by culturing CD14+ monocytes and their stimulation with any of IFN-{gamma}, IL-4, or IL-6 cytokines. Polarized macrophages were immunophenotyped using flow cytometry, and their expression of the selected genes were measured using qPCR. Finally, the proangiogenic capacity of the cells was assessed in an in vitro 3-D endothelial tubule formation assay, containing GFP-expressing human retinal endothelial cells, pericytes, and pro-angiogenic growth factors. ResultsIL-4 and IL-6 induce distinct M2-like phenotypes in macrophages with mixed pro- and anti-angiogenic gene expressions. Hyperglycemia has a mild negative effect on the expression of M2-associated markers, however it does not significantly affect the angiogenic properties of macrophages. ConclusionOur data support the concept of a spectrum model for macrophage polarization, indicating that the angiogenic status of polarized macrophages is not limited to the M2-phenotype, but is rather mediated by microenvironmental cues, and can result in diverse phenotypic characteristics. The effect of hyperglycemia on the angiogenic capacity of macrophages requires more comprehensive investigation.

immunology↗

bioRxiv2022

Did variants in inborn errors of immunity genes contribute to the extinction of Neanderthals?

Neanderthals were a species of archaic human that became extinct around 40,000 years ago. Modern humans have inherited 1-6% of Neanderthal DNA as a result of interbreeding with the Neanderthals. These inherited Neanderthal genes have paradoxical influences, while some can provide protection to viral infections, some others are associated with autoimmune/auto-inflammatory diseases. We hypothesized that genetic variants with strong detrimental effects on the function of the immune system could potentially contributed to the extinction of the Neanderthal population. In modern humans more than 450 genes are associated with inborn errors of immunity (IEI). We used the publically available genome information from a Neanderthal from the Altai mountains and filtered for potentially damaging variants that were present in genes associated with IEI, and checked whether these variants were present in the genomes of the Denisovan, Vindija and Chagyrskaya Neanderthals. We identified 24 homozygous variants and 15 heterozygous variants in IEI-related genes in the Altai Neanderthal. Interestingly, two homozygous variants in the UNC13D gene and one variant in the MOGS gene were present in all archaic genomes. Defects in the UNC13D gene are known to cause a severe and often fatal disease called hemophagocytic lymphohistiocystosis (HLH). One of these variants p.(Asn943Ser) has been reported in patients with HLH. Variants in MOGS are associated with glycosylation defects in the immune system affecting the susceptibility for infections. So, although we do not know exactly the functional impact yet, these three variants could have resulted in an increased susceptibility to severe diseases, and may have contributed to the extinction of Neanderthals after exposure to specific infections.

evolutionary biology↗