Biology subjects

Boudreau, J.

Publications and source records attributed to Boudreau, J..

5 recordsLinked to original sources

bioRxiv2025

Effective allogeneic natural killer cell therapy for pancreatic adenocarcinoma avails conserved activating receptors and evades HLA I-driven inhibition

BackgroundAt diagnosis, [~]80% of pancreatic ductal adenocarcinomas (PDAC) have metastasized. Relapse is thus common even among patients that undergo surgical resection, the only curative option. PDAC progresses rapidly, and existing immunotherapies have been ineffective. We hypothesized that natural killer (NK) cell immunotherapies could be effective against PDAC because they recognize conserved and heterogeneous features associated with cellular stress and transformation, and can seek out metastases distal to the primary tumour site. Here, we aim to define the key features of NK cells as effective agents for PDAC immunotherapy. MethodsWe used TCGA PDAC Firehose data and flow cytometry to predict and measure the most common activating or inhibitory ligands available on PDAC for NK cell activation. To ascertain how the tumour might alter expression of these ligands during treatment, inflammation or immune pressure, we measured expression of NK ligands at rest, or after exposure to immune cells or inflammation. To test and rank the functional importance of these dynamic ligands in the recognition, killing and control of PDAC< we used co-culture, antibody-blocking and an NK-competent humanized mouse model. ResultsLeveraging the known sequential acquisition of mutations as a surrogate for disease progression, we observed a progressive loss of transcript expression for activating NK cell ligands and chemoattractants. Exposure of PDAC to NK cells or IFN-{gamma}, an inflammatory stimulus, drove dynamic changes in expression of both activating and inhibitory ligands. In vitro co-culture assays revealed a redundancy in the activating receptors engaged in NK:PDAC interactions, but that HLA-KIR signalling dominantly interrupted anti-PDAC activity. In NK-competent humanized mice, adoptively transferred, unselected, unmodified NK cells slowed tumour growth in a dose-dependent manner, but NK cells selected to avoid HLA I-driven inhibition were the most competent effectors for PDAC control. ConclusionsAlthough there is redundancy among activating ligand:receptor pairs for recognizing PDAC tumours, but interactions between KIR and HLA define the extent to which anti-tumour activity can proceed. During tumour progression, and in response to immunotherapy. NK:tumour interactions drive upregulation of HLA I molecules. Thus, educated NK cells from HLA I-disparate donors may be the most effective allogeneic NK immunotherapy for PDAC. What is already known on this topicNK cells can be safely transferred across allogeneic barriers, so allogeneic therapy is possible. Since PDAC tumours progress very rapidly, there is insufficient time for engineered cell therapies. Although PDAC is typically considered to be an immunologically "cold" tumour, more recent studies have revealed that sub-tumour microenvironments can contain clusters of immune cells, and that the presence of immune cells in PDAC is associated with good prognosis. What this study addsWe explore how the naturally-occurring heterogeneity of activating and inhibitory receptor expression with and between individuals impacts recognition of PDAC tumour cells. We find that the natural cytotoxicity receptors and NKG2D are among the most likely activating receptors to be expressed on NK cells responding to PDAC. However, interactions between inhibitory killer immunoglobulin-like receptors (KIR) and class I human leukocyte antigens (HLA) dominantly inhibit NK cell killing. To enable NK cell reactivity without the liability of inhibition, we demonstrate that NK cells can be selected intentionally from allogeneic HLA-mismatched donors, where they retain programmed functionality, but are ignorant to the HLA-driven signals for inhibition present on the tumour cells. How this study might affect research, practice or policyDiversity among NK cell functions is driven by interactions between HLA I molecules and KIR, with the remaining receptor-ligand partnerships mostly conserved across people. KIR:HLA I interactions are predictable, and there is a limited range of potential combinations, so definitions of key functions would empower mass-production of NK cells from a limited range of healthy donors that could be used as off-the-shelf cellular immunotherapy. Our study provides key exclusion criteria that will inform these selections. Lee Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/677560v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@f6ed8forg.highwire.dtl.DTLVardef@1667904org.highwire.dtl.DTLVardef@9330ccorg.highwire.dtl.DTLVardef@168c85a_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Persistent glycolysis defines the foreign body response to polymeric implants.

Non-degradable polymeric implantable medical devices are a mainstay of modern healthcare but can frequently lead to severe complications. These complications are largely attributable to the foreign body response (FBR), which is characterized by excessive inflammation and fibrosis in response to implanted materials. The pathologic mechanisms underpinning the FBR remain elusive; however, metabolism is increasingly regarded as a critical regulator of innate immune function. We conducted comprehensive metabolic profiling of implant-associated macrophages and multinucleated giant cells in response to the subcutaneous implantation of clinically relevant implantable materials in a mouse model of implant fibrosis. Leveraging novel metabolic characterization methods for analysis of both metabolic dependence and enzyme expression in heterogeneous peri-implant tissues, we demonstrate that peri-implant macrophages are glycolytic at least up to six weeks post-implantation. Glycolytically dependent peri-implant macrophages expression of glucose transporter 1 (GLUT1) increased temporally and with proximity to the implant-tissue interface. Paired rate-limiting metabolic enzyme expression analysis showed notable increases in biosynthetic pathways (G6PD and ACC1), matched with increased mitochondrial staining intensity in GLUT1Hi cells at chronic timepoints, which were not notable at early timepoints. Notably, we identified a glycolytic dependence of multinucleated macrophages associated with polymeric materials: these cells expressed higher levels of GLUT1 than mononuclear macrophages of comparable metabolic phenotype. Our findings highlight GLUT1-dependent glycolysis as the definitive metabolic system used by peri-implant macrophages and multinucleated cells in the FBR, highlighting this pathway as a potential target for the development of novel therapeutic approaches.

immunology↗

bioRxiv2022

FMRI complexity correlates with tau-PET in Late-Onset and Autosomal Dominant Alzheimer's Disease

Neurofibrillary tangle pathology detected with tau-PET correlates closely with neuronal injury and cognitive symptoms in Alzheimers disease (AD). Complexity of rs-fMRI time-series, measured by entropy values, have recently been reported to decrease with aging, APOE {varepsilon}4 genotype and cognitive decline in AD. Here we hypothesize that the complexity of BOLD signals provides an index for tau-related neuronal injury and cognitive decline in the AD process. Data were obtained from the Alzheimers Disease Neuroimaging Initiative phase 3 (ADNI3) and the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) study, including cognitively normal elderly controls, persons with late onset AD (LOAD) and early onset autosomal dominant AD (ADAD) patients and their relatives. Our cohort consisted of a sample of 147 subjects from ADNI3 and 41 subjects from EEAJ with T1 structural, tau-PET (tracer: 18F-AV1451) and fMRI scans. Correlations between SUVR tau-PET and multi-scale entropy (MSE) were calculated voxelwise as well as for standard automated anatomical labeling (AAL) atlas regions while accounting for age, gender, and regional gray matter volume. Potential pathways relating MSE to cognitive function mediated through tau-PET were assessed by path analysis. We found significant negative correlations between low frequency MSE and tau-PET measures in medial temporal lobe, in both ADNI3 and EEAJ cohorts. Furthermore, low frequency MSE showed significant associations with the Clinical Dementia Rating (CDR) scale and the Mini-Mental State Status Exam (MMSE) scores in both ADNI3 and EEAJ cohorts, which were largely mediated through the tau-PET signal. Correlations of MSE with tau-PET in temporal lobes support our hypothesis that the complexity of rs-fMRI is associated with regional tau protein accumulation. Furthermore, the association of MSE with CDR and MMSE, mediated by tau-PET, in disease relevant areas suggests that a reduction in MSE is indicative of decreased information processing capacity and cognitive decline in AD processes.

neuroscience↗

bioRxiv2022

Visual Perception of 3D Space and Shape in Time - Part II: 3D Space Perception with Holographic Depth

Visual perception plays a critical role in navigating 3D space and extracting semantic information crucial to survival. Even though visual stimulation on the retina is fundamentally 2D, we seem to perceive the world around us in vivid 3D effortlessly. This reconstructed 3D space is allocentric and faithfully represents the external 3D world. How can we recreate stable 3D visual space so promptly and reliably? To solve this mystery, we have developed new concepts MePMoS (Memory-Prediction-Motion-Sensing) and NHT (Neural Holography Tomography). These models state that visual signal processing must be primarily top-down, starting from memory and prediction. Our brains predict and construct the expected 3D space holographically using traveling alpha brainwaves. Thus, 3D space is represented by the three time signals in three directions. To test this hypothesis, we designed reaction time (RT) experiments to observe predicted space-to-time conversion, especially as a function of distance. We placed LED strips on a horizontal plane to cover distances from close up to 2.5 m or 5 m, either using a 1D or a 2D lattice. Participants were instructed to promptly report observed LED patterns at various distances. As expected, stimulation at the fixation cue location always gave the fastest RT. Additional RT delays were proportional to the distance from the cue. Furthermore, both covert attention (without eye movements) and overt attention (with eye movements) created the same RT delays, and both binocular and monocular views resulted in the same RTs. These findings strongly support our predictions, in which the observed RT-depth dependence is indicative of the spatiotemporal conversion required for constructing allocentric 3D space. After all, we perceive and measure 3D space by time as Einstein postulated a century ago.

neuroscience↗

bioRxiv2018

A functional study of all 40 C. elegans insulin-like peptides

The human genome encodes ten insulin-like genes, whereas the C. elegans genome remarkably encodes forty insulin-like genes. The roles of insulin/insulin-like peptide ligands (INS) in C. elegans are not well understood. The functional redundancy of the forty INS genes makes it challenging to address their functions by using knock out strategies. Here, we individually overexpressed each of the forty ins genes pan-neuronally, and monitored multiple phenotypes including: L1 arrest life span, neuroblast divisions under L1 arrest, dauer formation and fat accumulation, as readouts to characterize the functions of each INS in vivo. Of the 40 INS peptides, we found functions for 35 INS peptides and functionally categorized each as agonists, antagonists or of pleiotropic function. In particular, we found that 9 of 16 agonistic INS peptides shortened L1 arrest life span and promoted neuroblast divisions during L1 arrest. Our study revealed that a subset of {beta}-class INS peptides that contain a distinct F peptide sequence are agonists. Our work is the first to categorize the structures of INS peptides and relate these structures to the functions of all forty INS peptides in vivo. Our findings will promote the study of insulin function on development, metabolism, and aging-related diseases.\n\nAuthor SummaryInsulin and insulin-like growth factors are found in all animals and regulate many physiological and developmental processes. The human genome has 10 insulin-like peptides including the well characterized insulin hormone. The nematode C. elegans has 40 insulin-like (INS) peptide genes. All 40 INS peptides have been knocked out but no single INS gene knock out resembles the loss of the C. elegans insulin receptor suggesting that the other INS peptides can compensate when one INS is lost. We have used a genetic approach to overexpress each of the 40 INS peptides in C. elegans and have identified in vivo function for 35 of the 40 INS peptides. Like the human insulin and IGF-1, C. elegans INS peptides are derived from a precursor protein and we have shown that INS peptides with an associated peptide called the F peptide are strong activators of the C. elegans insulin-like receptor. We also identified several INS peptides that inhibit the insulin-like receptor and these inhibitory INS peptides may have therapeutic potential.

genetics↗