Biology subjects

Lucas, C.-H. G.

Publications and source records attributed to Lucas, C.-H. G..

6 recordsLinked to original sources

bioRxiv2026

A generative reference grammar of healthy TCR repertoires reveals cancer-associated immune remodeling

T-cell receptor (TCR) repertoires record how adaptive immunity is organized and how cancer and therapy reshape it, but this signal is hard to read: treatment-associated change is entangled with the V(D)J recombination constraints that shape every repertoire. We present CRAFT (Cancer Repertoire Anomaly Finding Transformer), a conditional sequence-to-sequence transformer that learns a nucleotide-level generative grammar of productive TCR-beta CDR3 sequences from healthy donors, conditioned on germline V(D)J assignments. A dual-head decoder mirrors the independence of V-D and D-J recombination, and curriculum training produces embeddings that define a healthy-reference coordinate system in which cancer-associated change appears as structured, measurable deviation. In proof-of-concept applications to a neoadjuvant checkpoint-blockade cohort sampled longitudinally across blood, and to serial single-cell profiling of T-cell subsets during oncolytic immunotherapy, CRAFT geometric metrics capture response-associated remodeling, including shifts in repertoire organization over time. On antigen-labeled benchmarks, CRAFT organizes specificity classes coherently, recovering structure that reflects shared antigen recognition.

cancer biology↗

bioRxiv2026

B7-H3-targeted natural killer cells effectively kill atypical teratoid / rhabdoid tumors and extend survival in orthotopic xenografts

BackgroundAtypical teratoid/rhabdoid tumors (AT/RTs) are the most common malignant CNS tumor in infants, and patients suffer from low survival rates and treatment-related morbidities. These tumors frequently overexpress the pan-cancer antigen B7-H3 (CD276), which can be targeted with immunotherapy. We hypothesized that adding a B7-H3-targeting cytotoxic chimeric antigen receptor (CAR) to NK cells can enhance killing against AT/RTs. MethodsWe designed a library of variable affinity B7-H3-targeted CARs, which were transduced into primary healthy donor-derived NK cells. We verified B7-H3 expression in a panel of AT/RT cell lines and further engineered luciferase and nuclear GFP-expressing AT/RT (CHLA-04, CHLA-06, BT12, BT37) as well as a CHLA-06-derived B7-H3 knockout. We tested CAR-NK cell functionality using in vitro co-culture cytotoxicity assays. We delivered anti-B7-H3 CAR-NK cells intratumorally or intracerebroventricularly (ICV) to AT/RT orthotopic xenografts and monitored for tumor growth and animal survival. ResultsB7-H3-targeted CAR-NK cells demonstrated target-specific cytotoxicity when compared to unmodified NK cells. Knockout of B7-H3 in target cells abolished the increased CAR-mediated target killing. When delivered intratumorally to CHLA-06 orthotopic xenograft-bearing mice, anti-B7-H3 CAR-NK cells eliminated tumor cells and prolonged survival. When CAR-NK cells were delivered ICV against a CNS disseminated tumor model of BT12, treated mice had significantly improved survival. ConclusionsAnti-B7-H3 CAR-NK cells effectively kill AT/RTs in multiple pre-clinical in vitro and in vivo models in an antigen-specific manner. Evidence of efficacy in translationally relevant models provides support for using B7-H3-targeting CAR-NK cells in high-risk AT/RT patients.

cancer biology↗

bioRxiv2025

Impact of Data Quality on Deep Learning Prediction of Spatial Transcriptomics from Histology Images

Spatial transcriptomic technologies enable high-throughput quantification of gene expression at specific locations across tissue sections, facilitating insights into the spatial organization of biological processes. However, high costs associated with these technologies have motivated the development of deep learning methods to predict spatial gene expression from inexpensive hematoxylin and eosin-stained histology images. While most efforts have focused on modifying model architectures to boost predictive performance, the influence of training data quality remains largely unexplored. Here, we investigate how variation in molecular and image data quality stemming from differences in spatial transcriptomic technologies impact deep learning-based gene expression prediction from histology images. To identify the aspects of data quality that impact predictive performance, we conducted in silico ablation experiments, which showed that increased sparsity and noise in molecular data degraded predictive performance, while in silico rescue experiments via imputation provided only limited improvements that failed to generalize beyond the test set. Likewise, reduced image resolution can degrade predictive performance and further impacts model interpretability. We further demonstrate that these data quality-driven effects are reproducible across multiple spatial transcriptomics datasets and remain consistent when using alternative feature extractors and model architectures. Overall, our results show how improving data quality provides an orthogonal strategy to tuning model architecture in spatial transcriptomics-based predictive modeling, highlighting the need to account for technology-specific limitations that directly impact data quality when developing predictive methodologies.

bioinformatics↗

bioRxiv2025

IL-6 underlies microenvironment immunosuppression and resistance to therapy in glioblastoma

The glioblastoma tumor immune microenvironment (TIME) is an immunosuppressive barrier to therapy that encumbers glioblastoma responses to immune checkpoint inhibition (ICI). Immunosuppressive cytokines, pro-tumor myeloid cells, and exhausted T-cells are hallmarks of the glioblastoma TIME. Here we integrate spatial and single-cell analyses of patient-matched human glioblastoma samples before and after ICI with genetic, immunologic, single-cell, and pharmacologic studies in preclinical models to reveal that interleukin-6 (IL-6) inhibition reprograms the glioblastoma TIME to sensitize mouse glioblastoma to ICI and radiotherapy. Rare human glioblastoma patients who achieve clinical responses to ICI have lower pre-treatment IL-6 levels compared to glioblastomas who do not respond to ICI. Immune stimulatory gene therapy suppresses IL-6 tumor levels in preclinical murine models of glioblastoma. Furthermore, survival was longer in Il-6 knockout mice with orthotopic SB28 glioblastoma relative to wild-type mice. IL-6 blockade with a neutralizing antibody transiently sensitizes mouse glioblastoma to anti-PD-1 by increasing MHCII+ monocytes, CD103+ migratory dendritic cells (DCs), CD11b+ conventional DCs, and effector CD8+ T cells, and decreasing immunosuppressive Tregs. To translate these findings to a combination treatment strategy for recurrent glioblastoma patients, we show that IL-6 blockade plus ICI durably sensitizes mouse glioblastoma to high-dose radiotherapy.

cancer biology↗

bioRxiv2024

The CoREST complex inhibitor, corin, leads to decreased tumor growth, increased cellular differentiation and extended lifespan in atypical teratoid rhabdoid tumor xenograft models

BackgroundAtypical teratoid rhabdoid tumor (ATRT) is the most common malignant brain tumor in infants, and more than 60% of children with ATRT die from their tumor. ATRT is associated with mutational inactivation/deletion of SMARCB1, a member of the SWI/SNF chromatin remodeling complex, suggesting that epigenetic events play a critical role in tumor development and progression. Moreover, disruption of SWI/SNF allows unopposed activity of epigenetic repressors, which contribute to tumorigenicity. We therefore explored the role of the CoREST repressor complex in ATRT. MethodsWe evaluated the effects of the bifunctional LSD1/HDAC1/2 small molecule CoREST inhibitor, corin, on ATRT tumor cell growth, apoptosis, differentiation, gene expression and chromatin accessibility. ResultsWe found that corin inhibited the growth of ATRT cells regardless of their epigenetic subgroup, and was associated with increased tumor cell apoptosis and differentiation. ATAC-seq showed increases in chromatin accessibility in corin-treated ATRT cells, with changes seen at genes associated with neuronal differentiation and synaptic function. RNA-seq confirmed increased expression of neuronal differentiation genes and decreased DNA replication/cell cycle-associated genes in ATRT cells treated with corin. Corin suppressed orthotopic ATRT tumor growth, leading to significant extension of lifespan. In addition, increased histone acetylation (H3K9ac, H3K27ac) and methylation (H3K4Me1) was seen in corin-treated ATRT orthotopic xenografts, consistent with on-target pharmacodynamics. ConclusionThe CoREST inhibitor, corin, suppresses tumor growth, induces differentiation, and promotes apoptosis in ATRT, leading to significantly increased survival of mice bearing ATRT orthotopic xenografts. Our results suggest a potential application of CoREST complex inhibitors in patients with ATRT. Key PointsO_LICoREST complex inhibition by corin leads to decreased cell growth and increased apoptosis in ATRT C_LIO_LICorin promotes chromatin accessibility and neuronal differentiation in ATRT C_LIO_LICorin inhibits tumor growth and extends lifespan in ATRT animal models C_LI Importance of the StudyLoss of function of SMARCB1 is a hallmark of ATRT which leads to dysfunction of the mammalian SWI/SNF complex and an inability to counteract epigenetic repressor complexes. The CoREST complex functions as a chromatin remodeling complex that represses neuronal differentiation genes during development. Inhibition of the CoREST complex by corin in ATRT leads to decreased tumor cell growth, induction of apoptosis and increased survival of mice bearing ATRT orthotopic xenografts. These changes are associated with increased chromatin accessibility and expression of genes associated with neuronal differentiation. Corin therefore reverses the primary block of differentiation that maintains a stem cell state in ATRT, which contributes to tumorigenesis. These studies significantly improve our understanding of how to therapeutically address the underlying epigenetic drivers of ATRT and support further development of corin for ATRT.

cancer biology↗

bioRxiv2023

NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy

Meningiomas are the most common primary intracranial tumors1-3. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental4,5. Resistance to radiotherapy is common in high-grade meningiomas6, and the cell types and signaling mechanisms driving meningioma tumorigenesis or resistance to radiotherapy are incompletely understood. Here we report NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and find NOTCH3+ meningioma mural cells are conserved across meningiomas from humans, dogs, and mice. NOTCH3+ cells are restricted to the perivascular niche during meningeal development and homeostasis and in low-grade meningiomas but are expressed throughout high-grade meningiomas that are resistant to radiotherapy. Integrating single-cell transcriptomics with lineage tracing and imaging approaches across mouse genetic and xenograft models, we show NOTCH3 drives tumor initiating capacity, cell proliferation, angiogenesis, and resistance to radiotherapy to increase meningioma growth and reduce survival. An antibody stabilizing the extracellular negative regulatory region of NOTCH37,8 blocks meningioma tumorigenesis and sensitizes meningiomas to radiotherapy, reducing tumor growth and improving survival in preclinical models. In summary, our results identify a conserved cell type and signaling mechanism that underlie meningioma tumorigenesis and resistance to radiotherapy, revealing a new therapeutic vulnerability to treat meningiomas that are resistant to standard interventions.

cancer biology↗