Biology subjects

Yang, J. C.

Publications and source records attributed to Yang, J. C..

10 recordsLinked to original sources

bioRxiv2026

HLA-A*11:01-Restricted T Cell Receptors Targeting Mutant NPM1 for Adoptive Cell Therapy in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy associated with a poor prognosis and an unmet need for more effective treatment options, particularly after relapse. One potential approach to address this need, which has been used successfully in solid tumors, is adoptive transfer of T cells engineered to express specific T cell receptors (TCRs). Particularly attractive are TCRs that can target epitopes derived from oncogenes on which cancer cells depend while sparing normal cells that do not harbor the mutation. One promising oncogenic target in AML is mutated nucleophosmin 1 (mtNPM1), present in up to 30% of AML cases. Most NPM1 mutations result in a common frameshifted sequence that generates peptides presented by several class I human leukocyte antigens (HLAs), such as HLA-A*11:01. In this study, we vaccinated HLA-A*11:01-transgenic mice with the mtNPM1 peptide AVEEVSLRK and isolated six functional TCRs from mtNPM1-reactive lymphocytes. When engineered into human T cells, two of these TCRs consistently mediated robust and specific lysis of an AML cell line and primary AML cells co-expressing HLA-A*11:01 and mtNPM1. Neither TCR recognized related human peptides, HLA-A*11:01-expressing normal peripheral blood mononuclear cells or stem/progenitor cells, or cells expressing diverse allogeneic HLAs, suggesting a low risk of cross-reactivity and alloreactivity. In an AML xenograft model, both TCRs controlled AML in hematopoietic organs, although extramedullary tumors emerged during treatment, potentially reflecting the aggressive behavior of the model that may not be representative of AML in patients. Together, these data suggest that the two TCRs represent strong candidates for further preclinical development in adoptive T cell therapy for NPM1-mutated, HLA-A*11:01-positive AML. These results also support the use of HLA-transgenic mice as a platform for generating TCRs targeting oncogene-derived epitopes in hematologic malignancies.

immunology↗

bioRxiv2025

Rapid enrichment of progenitor exhausted neoantigen-specific CD8 T cells from peripheral blood

Neoantigen-reactive peripheral blood lymphocytes (NeoPBL) are tumor-specific T cells found at ultra-low frequencies in the blood. Unlike tumor-infiltrating lymphocytes (TIL), NeoPBL exist in a favorable less dysfunctional phenotypic state in vivo, but their rarity has precluded their effective use as cell therapy. Leveraging a priori knowledge of bona fide neoantigens, we combined high-intensity neoantigen stimulation with bead extraction of neoantigen peptide-pulsed target cells to enable the enrichment of NeoPBL to frequencies comparable to ex vivo cultured TIL over a 28-day period. Throughout this process, NeoPBL demonstrate specific reactivity against autologous tumor organoids and maintain memory-like features, including elevated expression of CD28 and TCF7. We additionally demonstrate that NeoPBL reactivity is polyclonal, encompassing multiple clonotypes that are detectable within in vivo TIL populations, underscoring physiological specificity for the targeted neoantigens. This streamlined process yields clinically relevant cell doses and enables identification and expansion of blood-derived neoantigen-specific TCRs. By potentially avoiding additional surgical risks and protracted delays of TIL and individualized TCR-engineered methods, the NeoPBL platform may have clinical and practical advantages. Ultimately, NeoPBL combines intrinsic cell fitness, minimal invasiveness and rapidity to potentially facilitate personalized adoptive cell therapy for cancer.

immunology↗

bioRxiv2024

The ZIP8 A391T Crohn's disease-linked risk variant induces colonic metal ion dyshomeostasis, microbiome compositional shifts, and inflammation

The pathogenesis of Crohns disease involves genetic and environmental factors, with the gut microbiome playing a crucial role. The Crohns disease-associated variant rs13107325 in the SLC39A8 gene results in an A391T substitution in the ZIP8 metal ion transporter and has previously been linked to alterations in the colonic microbiome in variant carriers. We hypothesized that the A391T substitution alters metal ion homeostasis in the colonic mucosal-luminal interface, thereby inducing dysbiosis which may promote intestinal inflammation. To evaluate this hypothesis, we generated a SLC39A8 A393T mouse model (matching human A391T). Consistent with an effect of the variant on ZIP8 function, homozygous A393T mice exhibited increased cobalt in the colonic mucosa, but reduced iron, zinc, manganese, cobalt, copper, and cadmium in the colonic lumen. We performed 16S rRNA gene sequencing of colon samples and histological scoring of colon tissue collected from the SLC39A8 A393T mouse model at different ages. We identified variant-linked effects on microbiome beta diversity in 2-month, 3-4 month, and 12-month old mice and spontaneous intestinal inflammation in 10-month but not 5-month old mice. Predicted pathway analysis of the microbiome samples revealed differential enrichment of iron-, zinc- and cobalt-dependent pathways in A393T mice compared to wild-type controls. These results suggest that the variant in SLC39A8 primarily restricts metal availability to the microbiota, resulting in compositions that can adapt to the environment, and that A393T-linked dysbiosis occurs prior to the onset of inflammation. This study paves the way for future studies investigating risk variants as microbiome-disease modifiers. NEW & NOTEWORTHYMice recapitulating the human A391T Crohns disease-linked risk variant in the SLC39A8-encoded ZIP8 transporter exhibit reduced luminal trace metals and an altered microbiome composition. The microbiome compositional shift occurs prior to the onset of spontaneous colonic inflammation. This study supports an emerging paradigm by which genetic risk for inflammatory bowel disease may confer disease susceptibility through modulation of the gut microbiome.

genomics↗

bioRxiv2024

Identification and Structural Characterization of a mutant KRAS-G12V specific TCR restricted by HLA-A3

Mutations in KRAS are some of the most common across multiple cancer types and are thus attractive targets for therapy. Recent studies demonstrated that mutant KRAS generates immunogenic neoantigens that can be targeted in adoptive T cell therapy in metastatic diseases. To expand mutant KRAS specific immunotherapies, it is critical to identify additional HLA-I allotypes that can present KRAS neoantigens and their cognate T cell receptors (TCR). Here, we identified a murine TCR specific to a KRAS-G12V neoantigen (7VVVGAVGVGK16) using a vaccination approach with transgenic mice expressing the common HLA-I allotype, HLA-A*03:01 (HLA-A3). This TCR demonstrated exquisite specificity for mutant G12V and not Wt KRAS peptides. To investigate the molecular basis for neoantigen recognition by This TCR, we determined its structure in complex with HLA-A3(G12V). G12V-TCR CDR3{beta} and CDR1 {beta} formed a hydrophobic pocket to interact with p6 Val of the G12V but not Wt KRAS peptide. To improve the tumor sensitivity of This TCR, we designed rational substitutions to improve TCR:HLA-A3 contacts. Two substitutions exhibited modest improvements in TCR binding to HLA-A3 (G12V), but did not sufficiently improve T cell sensitivity for further clinical development. Our study provides mechanistic insight into how TCRs detect neoantigens and reveals the challenges in targeting KRAS-G12V mutations. [203]

immunology↗

bioRxiv2024

Modular Phoneme Processing in Human Superior Temporal Gyrus

Modular organization is fundamental to cortical processing, but its presence is human association cortex is unknown. We characterized phoneme processing with 128-1024 channel micro-arrays at 50-200m pitch on superior temporal gyrus of 7 patients. High gamma responses were highly correlated within [~]1.7mm diameter modules, sharply delineated from adjacent modules with distinct time-courses and phoneme-selectivity. We suggest that receptive language cortex may be organized in discrete processing modules.

neuroscience↗

bioRxiv2023

The Brain Electroencephalogram Microdisplay for Precision Neurosurgery

Brain surgeries are among the most delicate clinical procedures and must be performed with the most technologically robust and advanced tools. When such surgical procedures are performed in functionally critical regions of the brain, functional mapping is applied as a standard practice that involves direct coordinated interactions between the neurosurgeon and the clinical neurology electrophysiology team. However, information flow during these interactions is commonly verbal as well as time consuming which in turn increases the duration and cost of the surgery, possibly compromising the patient outcomes. Additionally, the grids that measure brain activity and identify the boundaries of pathological versus functional brain regions suffer from low resolution (3-10 mm contact to contact spacing) with limited conformity to the brain surface. Here, we introduce a brain intracranial electroencephalogram microdisplay (Brain-iEEG-microdisplay) which conforms to the brain to measure the brain activity and display changes in near real-time (40 Hz refresh rate) on the surface of the brain in the surgical field. We used scalable engineered gallium nitride (GaN) substrates with 6" diameter to fabricate, encapsulate, and release free-standing arrays of up to 2048 GaN light emitting diodes (LEDs) in polyimide substrates. We then laminated the LED arrays on the back of micro-electrocorticography (ECoG) platinum nanorod grids (PtNRGrids) and developed hardware and software to perform near real-time intracranial EEG analysis and activation of light patterns that correspond to specific cortical activities. Using the Brain-iEEG-microdisplay, we precisely ideFSntified and displayed important cortical landmarks and pharmacologically induced pathological activities. In the rat model, we identified and displayed individual cortical columns corresponding to individual whiskers and the near real-time evolution of epileptic discharges. In the pig animal model, we demonstrated near real-time mapping and display of cortical functional boundaries using somatosensory evoked potentials (SSEP) and display of responses to direct electrical stimulation (DES) from the surface or within the brain tissue. Using a dual-color Brain-iEEG-microdisplay, we demonstrated co-registration of the functional cortical boundaries with one color and displayed the evolution of electrical potentials associated with epileptiform activity with another color. The Brain-iEEG-microdisplay holds the promise of increasing the efficiency of diagnosis and possibly surgical treatment, thereby reducing the cost and improving patient outcomes which would mark a major advancement in neurosurgery. These advances can also be translated to broader applications in neuro-oncology and neurophysiology. One Sentence SummaryA brain intracranial electroencephalogram microdisplay (Brain-iEEG-microdisplay) measures and displays real-time brain activity in the surgical field.

neuroscience↗

bioRxiv2022

Flexible, Scalable, High Channel Count Stereo-Electrode for Recording in the Human Brain

Over the past decade, stereotactically placed electrodes have become the gold standard for deep brain recording and stimulation for a wide variety of neurological and psychiatric diseases. Current electrodes, however, are limited in their spatial resolution and ability to record from small populations of neurons, let alone individual neurons. Here, we report on a novel, reconfigurable, monolithically integrated human-grade flexible depth electrode capable of recording from up to 128 channels and able to record at a depth of 10 cm in brain tissue. This thin, stylet-guided depth electrode is capable of recording local field potentials and single unit neuronal activity (action potentials), validated across species. This device represents a major new advance in manufacturing and design approaches which extends the capabilities of a mainstay technology in clinical neurology. One-Sentence SummaryA human-grade thin-film depth electrode offers new opportunities in spatial and temporal resolution for recording brain activity.

neuroscience↗

bioRxiv2020

Effectively control of viral disease outbreak in shrimp culture system by selective predation

Due to the limited understanding of the characteristics of predator-pathogen-prey interactions, few attempts to use selective predation for controlling diseases in prey populations have been successful. The global pandemic of white spot syndrome (WSS), caused by white spot syndrome virus (WSSV), causes devastating economic losses in farmed shrimp production. Currently, there is no effective control for WSS. Here, we determined the transmission dynamics of WSSV and the feeding ability and selectivity of fish on healthy, infected and dead shrimp by experiments and mathematical modeling. Accordingly, we developed a novel and convenient shrimp cultural ecosystem, which that effectively prevented WSS outbreaks, by introducing aquaculture fish species. This provides a scheme for developing control strategies for viral diseases with high transmission rate.

ecology↗

bioRxiv2020

Proteogenomic analysis unveils the HLA Class I presented immunopeptidome in melanoma and EGFR mutant lung adenocarcinoma

Immune checkpoint inhibitor and adoptive lymphocyte transfer-based therapies have shown great therapeutic potential for cancers with high tumor mutation burden (TMB). Here, we employed mass spectrometry (MS)-based proteogenomic large-scale profiling to identify potential immunogenic human leukocyte antigen (HLA) Class I-presented peptides in both melanoma, a "hot tumor" with high TMB, and EGFR mutant lung adenocarcinoma, a "cold tumor" with low TMB. We identified several classes of neopeptides, including mutated neoantigens and more than 1000 post-translationally modified peptides representing 58 different PTMs. We constructed a cancer germline (CG) antigen database with 285 antigens and identified 42 Class I-presented CG antigens. Finally, we developed a non-canonical peptide discovery pipeline to identify 44 lncRNA-derived peptides and validated Class I binding for select neopeptides. We provide direct evidence of HLA Class I presentation of a large number of neopeptides for potential vaccine or adoptive cell therapy in melanoma and mutant EGFR lung cancer.

immunology↗

bioRxiv2019

Microscale physiological events on the human cortical surface detected with PEDOT:PSS Electrodes

Despite ongoing advancements in our understanding of the local single-cellular and network-level activity of neuronal populations in the human brain, extraordinarily little is known about their intermediate microscale local circuit dynamics. Here, we utilized ultrahigh density microelectrode arrays and a rare opportunity to perform intracranial recordings across multiple cortical areas in human participants to discover three distinct classes of cortical activity that are not locked to ongoing natural brain rhythmic activity. The first included fast waveforms similar to extracellular single unit activity. The other two types were discrete events with slower waveform dynamics and were found preferentially in upper layers of the grey matter. They were also observed in rodents, non-human primates, and semi-chronic recordings in humans via laminar and Utah array microelectrodes. The rates of all three events were selectively modulated by auditory and electrical stimuli, pharmacological manipulation, and cold saline application and had small causal co-occurrences. These results suggest that with the proper combination of high resolution microelectrodes and analytic techniques it is possible to capture neuronal dynamics that lay between somatic action potentials and aggregate population activity and that understanding these intermediate microscale dynamics may reveal important details of the full circuit behavior in human cognition.

neuroscience↗