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Immunity Nov 2023The accurate selection of neoantigens that bind to class I human leukocyte antigen (HLA) and are recognized by autologous T cells is a crucial step in many cancer...
The accurate selection of neoantigens that bind to class I human leukocyte antigen (HLA) and are recognized by autologous T cells is a crucial step in many cancer immunotherapy pipelines. We reprocessed whole-exome sequencing and RNA sequencing (RNA-seq) data from 120 cancer patients from two external large-scale neoantigen immunogenicity screening assays combined with an in-house dataset of 11 patients and identified 46,017 somatic single-nucleotide variant mutations and 1,781,445 neo-peptides, of which 212 mutations and 178 neo-peptides were immunogenic. Beyond features commonly used for neoantigen prioritization, factors such as the location of neo-peptides within protein HLA presentation hotspots, binding promiscuity, and the role of the mutated gene in oncogenicity were predictive for immunogenicity. The classifiers accurately predicted neoantigen immunogenicity across datasets and improved their ranking by up to 30%. Besides insights into machine learning methods for neoantigen ranking, we have provided homogenized datasets valuable for developing and benchmarking companion algorithms for neoantigen-based immunotherapies.
Topics: Humans; Antigens, Neoplasm; Neoplasms; Histocompatibility Antigens Class I; Machine Learning; Peptides; Immunotherapy
PubMed: 37816353
DOI: 10.1016/j.immuni.2023.09.002 -
Nature Dec 2023The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs. Retinal cell types may have evolved to accommodate... (Comparative Study)
Comparative Study
The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs. Retinal cell types may have evolved to accommodate these varied needs, but this has not been systematically studied. Here we generated and integrated single-cell transcriptomic atlases of the retina from 17 species: humans, two non-human primates, four rodents, three ungulates, opossum, ferret, tree shrew, a bird, a reptile, a teleost fish and a lamprey. We found high molecular conservation of the six retinal cell classes (photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells (RGCs) and Müller glia), with transcriptomic variation across species related to evolutionary distance. Major subclasses were also conserved, whereas variation among cell types within classes or subclasses was more pronounced. However, an integrative analysis revealed that numerous cell types are shared across species, based on conserved gene expression programmes that are likely to trace back to an early ancestral vertebrate. The degree of variation among cell types increased from the outer retina (photoreceptors) to the inner retina (RGCs), suggesting that evolution acts preferentially to shape the retinal output. Finally, we identified rodent orthologues of midget RGCs, which comprise more than 80% of RGCs in the human retina, subserve high-acuity vision, and were previously believed to be restricted to primates. By contrast, the mouse orthologues have large receptive fields and comprise around 2% of mouse RGCs. Projections of both primate and mouse orthologous types are overrepresented in the thalamus, which supplies the primary visual cortex. We suggest that midget RGCs are not primate innovations, but are descendants of evolutionarily ancient types that decreased in size and increased in number as primates evolved, thereby facilitating high visual acuity and increased cortical processing of visual information.
Topics: Animals; Humans; Neurons; Retina; Retinal Ganglion Cells; Single-Cell Gene Expression Analysis; Vertebrates; Vision, Ocular; Species Specificity; Biological Evolution; Amacrine Cells; Photoreceptor Cells; Ependymoglial Cells; Retinal Bipolar Cells; Visual Perception
PubMed: 38092908
DOI: 10.1038/s41586-023-06638-9 -
Biomedicines Dec 2023Almost a quarter of a millennium after the discovery of an acidic substance in sour milk by Swedish chemist Carl Wilhelm Scheele and more than 100 years after the... (Review)
Review
Almost a quarter of a millennium after the discovery of an acidic substance in sour milk by Swedish chemist Carl Wilhelm Scheele and more than 100 years after the demonstration of a tight connection between this lactic acid and tissue hypoxia in shock, we are still surrounded by false beliefs and misunderstandings regarding this fascinating molecule. Common perceptions of lactate, the conjugate base of lactic acid, as a plain waste product of anaerobic metabolism and a marker of cellular distress could not be further from the truth. Lactate is formed and utilized continuously by our cells, even under fully aerobic conditions, in large quantities, and although marked hyperlactatemia is always a red flag in our patients, not all these conditions are life-threatening and vice versa-not all critically ill patients have hyperlactatemia. Lactate also does not promote acidosis by itself; it is not toxic, nor is it a metabolic renegade. On the contrary, it has many beneficial properties, and an interpretation of hyperlactatemia might be trickier than we tend to think. The aim of this article is to debunk some of the deeply rooted myths regarding this fascinating molecule.
PubMed: 38137413
DOI: 10.3390/biomedicines11123192 -
Nature Apr 2024Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative...
Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative interface between sensory and metabolic modalities remain unknown, despite primary thermoceptive neurons in the pontine parabrachial nucleus becoming well characterized. Tanycytes are a specialized cell type along the wall of the third ventricle that bidirectionally transport hormones and signalling molecules between the brain's parenchyma and ventricular system. Here we show that tanycytes are activated upon acute thermal challenge and are necessary to reduce food intake afterwards. Virus-mediated gene manipulation and circuit mapping showed that thermosensing glutamatergic neurons of the parabrachial nucleus innervate tanycytes either directly or through second-order hypothalamic neurons. Heat-dependent Fos expression in tanycytes suggested their ability to produce signalling molecules, including vascular endothelial growth factor A (VEGFA). Instead of discharging VEGFA into the cerebrospinal fluid for a systemic effect, VEGFA was released along the parenchymal processes of tanycytes in the arcuate nucleus. VEGFA then increased the spike threshold of Flt1-expressing dopamine and agouti-related peptide (Agrp)-containing neurons, thus priming net anorexigenic output. Indeed, both acute heat and the chemogenetic activation of glutamatergic parabrachial neurons at thermoneutrality reduced food intake for hours, in a manner that is sensitive to both Vegfa loss-of-function and blockage of vesicle-associated membrane protein 2 (VAMP2)-dependent exocytosis from tanycytes. Overall, we define a multimodal neurocircuit in which tanycytes link parabrachial sensory relay to the long-term enforcement of a metabolic code.
Topics: Animals; Female; Male; Mice; Agouti-Related Protein; Arcuate Nucleus of Hypothalamus; Brain Stem; Dopamine; Eating; Ependymoglial Cells; Feeding Behavior; Glutamic Acid; Hot Temperature; Hypothalamus; Neural Pathways; Neurons; Parabrachial Nucleus; Thermosensing; Time Factors; Vascular Endothelial Growth Factor A
PubMed: 38538787
DOI: 10.1038/s41586-024-07232-3 -
Molecular Therapy. Methods & Clinical... Dec 2023Chimeric antigen receptor (CAR) T cells targeting CD19 B cells have demonstrated efficacy in refractory systemic lupus erythematosus (SLE). Although initial clinical...
Chimeric antigen receptor (CAR) T cells targeting CD19 B cells have demonstrated efficacy in refractory systemic lupus erythematosus (SLE). Although initial clinical data suggest that anti-CD19 CAR T cell therapy is well tolerated and highly effective, the immunologic consequences of CAR T cell therapy in SLE patients remain unclear. We profiled serum in six refractory SLE patients prior to and 3 months following CAR T cell infusion. Three months post T cell infusion, the inflammatory cytokines IL-6 and TNFα decreased in patient sera. This was accompanied by elevations in serum IL-7 and BAFF. Furthermore, SLE-associated antibodies dropped profoundly in five of six patients. Last, consistent with other reports of CD19 CAR T therapy in B cell malignancies, we were able to show marginal impact of anti-CD19 CART therapy on pre-existing humoral immune responses in SLE patients. Together, these results provide insights into the mechanisms of efficacy of anti-CD19 CAR T cell therapy in SLE.
PubMed: 37744005
DOI: 10.1016/j.omtm.2023.08.023 -
Investigative Ophthalmology & Visual... Jul 2023Diabetic macular edema (DME) is a common complication of diabetic retinopathy and is the leading cause of vision loss in diabetic patients. Various factors, such as... (Review)
Review
Diabetic macular edema (DME) is a common complication of diabetic retinopathy and is the leading cause of vision loss in diabetic patients. Various factors, such as metabolic disorders and inflammation caused by hyperglycemia, are involved in the occurrence and development of DME, but the specific mechanism is still unclear. Müller cells are a type of macroglial cell unique to the fundus, distributed throughout the retina, and they play a unique role in retinal homeostasis. This article reviews the role of Müller cells in the pathological process of DME and the research progress in the treatment of DME by targeting Müller cells through gene therapy.
Topics: Humans; Diabetic Retinopathy; Macular Edema; Ependymoglial Cells; Retina; Fundus Oculi; Diabetes Mellitus
PubMed: 37418272
DOI: 10.1167/iovs.64.10.8 -
Annual Review of Vision Science May 2024The continuous function of vertebrate photoreceptors requires regeneration of their visual pigment following its destruction upon activation by light (photobleaching).... (Review)
Review
The continuous function of vertebrate photoreceptors requires regeneration of their visual pigment following its destruction upon activation by light (photobleaching). For rods, the chromophore required for the regeneration of rhodopsin is derived from the adjacent retinal pigmented epithelium (RPE) cells through a series of reactions collectively known as the RPE visual cycle. Mounting biochemical and functional evidence demonstrates that, for cones, pigment regeneration is supported by the parallel supply with chromophore by two pathways-the canonical RPE visual cycle and a second, cone-specific retina visual cycle that involves the Müller glial cells in the neural retina. In this article, we review historical information that led to the discovery of the retina visual cycle and discuss what is currently known about the reactions and molecular components of this pathway and its functional role in supporting cone-mediated vision.
PubMed: 38724080
DOI: 10.1146/annurev-vision-100820-083937 -
Stem Cell Reports Dec 2023In mammals, loss of retinal cells due to disease or trauma is an irreversible process that can lead to blindness. Interestingly, regeneration of retinal neurons is a...
In mammals, loss of retinal cells due to disease or trauma is an irreversible process that can lead to blindness. Interestingly, regeneration of retinal neurons is a well established process in some non-mammalian vertebrates and is driven by the Müller glia (MG), which are able to re-enter the cell cycle and reprogram into neurogenic progenitors upon retinal injury or disease. Progress has been made to restore this mechanism in mammals to promote retinal regeneration: MG can be stimulated to generate new neurons in vivo in the adult mouse retina after the over-expression of the pro-neural transcription factor Ascl1. In this study, we applied the same strategy to reprogram human MG derived from fetal retina and retinal organoids into neurons. Combining single cell RNA sequencing, single cell ATAC sequencing, immunofluorescence, and electrophysiology we demonstrate that human MG can be reprogrammed into neurogenic cells in vitro.
Topics: Animals; Mice; Humans; Neuroglia; Neurogenesis; Neurons; Retina; Mammals; Ependymoglial Cells; Cell Proliferation; Basic Helix-Loop-Helix Transcription Factors
PubMed: 38039971
DOI: 10.1016/j.stemcr.2023.10.021 -
Nature Communications Aug 2023TGFβ signaling is associated with non-response to immune checkpoint blockade in patients with advanced cancers, particularly in the immune-excluded phenotype. While...
TGFβ signaling is associated with non-response to immune checkpoint blockade in patients with advanced cancers, particularly in the immune-excluded phenotype. While previous work demonstrates that converting tumors from excluded to inflamed phenotypes requires attenuation of PD-L1 and TGFβ signaling, the underlying cellular mechanisms remain unclear. Here, we show that TGFβ and PD-L1 restrain intratumoral stem cell-like CD8 T cell (T) expansion and replacement of progenitor-exhausted and dysfunctional CD8 T cells with non-exhausted T effector cells in the EMT6 tumor model in female mice. Upon combined TGFβ/PD-L1 blockade IFNγ CD8 T effector cells show enhanced motility and accumulate in the tumor. Ensuing IFNγ signaling transforms myeloid, stromal, and tumor niches to yield an immune-supportive ecosystem. Blocking IFNγ abolishes the anti-PD-L1/anti-TGFβ therapy efficacy. Our data suggest that TGFβ works with PD-L1 to prevent T expansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state.
Topics: Female; Animals; Mice; Cell Differentiation; CD8-Positive T-Lymphocytes; Stem Cells; B7-H1 Antigen; Transforming Growth Factor beta; Interferon-gamma; T-Cell Exhaustion; Immune Checkpoint Inhibitors; Mice, Inbred BALB C; Cell Line, Tumor; Breast Neoplasms; RNA-Seq
PubMed: 37543621
DOI: 10.1038/s41467-023-40398-4