Biology subjects

Chiocca, E. A.

Publications and source records attributed to Chiocca, E. A..

7 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↗

bioRxiv2024

Longitudinal analysis of glioblastoma response to oncolytic HSV1 guides PLX3397 combination for enhanced viral permissiveness

Clinical trial data underscores the need to improve oncolytic virus (OV) distribution within tumors, a challenge compounded by the lack of predictive biomarkers and limited opportunities for post-treatment analysis. To decipher the factors influencing treatment outcomes, we employed multimodal bioluminescence imaging (MM-BLI) in conjunction with magnetic resonance imaging (MRI) to monitor OV infection, replication, and tumor viability in orthotopic brain glioma mouse models. This approach revealed two distinct therapeutic responses: "Responders" with tumor regression and "Non-Responders" with tumor progression. In-depth analysis of individual brains from both groups uncovered dynamic interactions between the OV and the tumor microenvironment, highlighting the involvement of Iba-1+ microglia and tumor necrosis in hindering OV distribution within the tumor. To address this, we incorporated a CSF-1 receptor inhibitor (PLX3397), which improved tumor control by enhancing OVs direct cytopathic effects and reducing microglial interference. Our findings highlight microglia as a significant barrier to effective OV therapy, suggesting that targeting brain-resident immune cells could enhance the therapeutic efficacy of OVs in resistant brain tumors.

bioengineering↗

bioRxiv2022

STING activation promotes robust immune response and tumor regression in glioblastoma models

Immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease. However, the aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive and remains largely refractory to current immunotherapeutic approaches. The cGAS-STING cytoplasmic double stranded DNA (dsDNA) sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties. Here, we investigated the status of the STING pathway in GBM and the modulation of the brain tumor microenvironment (TME) with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature. We show that human GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils and NK populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100-loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. Responses to treatment were abolished by NK cell depletion. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants the further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, CAR T cells, NK therapies or immune checkpoint blockade. Significance statementModulation of the immune microenvironment is critical for immunosuppressive and therapy refractory tumors like glioblastoma. Activation of the STING pathway deeply remodels the brain tumor environment and attracts innate immune cells and natural killer cell populations, producing a robust antitumor effect with long-term immune memory. We further show that human glioblastoma tissue can respond to the therapy and lay the foundations for combined intracranial immunotherapies by using crosslinked biodegradable brain implants.

cancer biology↗

bioRxiv2021

Decrowding Expansion Pathology: Unmasking Previously Invisible Nanostructures and Cells in Intact Human Brain Pathology Specimens

Proteins are densely packed in cells and tissues, where they form complex nanostructures. Expansion microscopy (ExM) variants have been used to separate proteins from each other in preserved biospecimens, improving antibody access to epitopes. Here we present an ExM variant, decrowding expansion pathology (dExPath), which can expand proteins away from each other in human brain pathology specimens, including formalin-fixed paraffin-embedded (FFPE) clinical specimens. Immunostaining of dExPath-expanded specimens reveals, with nanoscale precision, previously unobserved cellular structures, as well as more continuous patterns of staining. This enhanced molecular staining results in observation of previously invisible disease marker-positive cell populations in human glioma specimens, with potential implications for tumor aggressiveness. dExPath results in improved fluorescence signals even as it eliminates lipofuscin-associated autofluorescence. Thus, this form of expansion-mediated protein decrowding may, through improved epitope access for antibodies, render immunohistochemistry more powerful in clinical science and diagnosis.

bioengineering↗

bioRxiv2020

BTP-7, a novel peptide for therapeutic targeting of malignant brain tumors

BackgroundTargeted therapies for malignant brain cancer that are currently available have little clinical activity, highlighting an urgent need for the development of novel precision medicines. Brevican (Bcan), a central nervous system (CNS)-specific extracellular matrix protein is upregulated in glioma cells. A brevican isoform lacking glycosylation, dg-Bcan, is a unique glioma marker and thus represents a valuable target for anti-cancer therapy. In this study, we aimed to find a versatile dg-Bcan specific ligand to facilitate glioma targeting. MethodsWe screened a D-peptide library to identify dg-Bcan-Targeting Peptide (BTP) candidates, which were characterized extensively through binding kinetic analyses, cell uptake tests and animal studies. ResultsThe top candidate, BTP-7 binds dg-Bcan with high affinity and specificity, is preferentially internalized by Bcan-expressing glioma cells and can cross the blood-brain barrier in vitro and in mice. Functionalization of camptothecin with BTP-7 led to increased drug delivery to intracranial glioblastoma and cytotoxicity in tumor tissues, as well as prolonged survival in tumor-bearing mice. Conclusiondg-Bcan is an attractive therapeutic target for high-grade gliomas, and BTP-7 represents a promising lead candidate for further development into novel targeted therapeutics. Key pointsO_LIBTP-7 is a high affinity peptide ligand for the dg-Bcan protein and Bcan-expressing cells. C_LIO_LIBTP-7 targets human intracranial GBM xenografts in mice. C_LIO_LIFunctionalization of a toxic anti-cancer drug with BTP-7 enables targeted delivery of the therapeutic to intracranial GBM in mice C_LI Importance of the StudyTargeted therapies for malignant brain cancer that are currently available have little clinical activity, highlighting an urgent need for the development of novel precision medicines that can selectively recognize and kill high-grade glioma tissues. A protein called dg-Bcan is an ideal target because it is present only in the extracellular matrix of high-grade glioma cells and is absent from normal brain tissues. Here, we describe the discovery of a novel dg-Bcan-Targeting Peptide, called BTP-7 that can bind specifically to high-grade glioma cells/tissues, and thus serve as a promising drug delivery vehicle.

bioengineering↗

bioRxiv2020

Redesigned Reporter Gene for Improved Proton Exchange-based Molecular MRI Contrast

Reporter gene imaging allows for non-invasive monitoring of molecular processes in living cells, providing insights on the mechanisms underlying pathology and therapy. A lysine-rich protein (LRP) chemical exchange saturation transfer (CEST) MRI reporter gene has previously been developed and used to image tumor cells, cardiac viral gene transfer, and oncolytic virotherapy. However, the highly repetitive nature of the LRP reporter gene sequence leads to DNA recombination events and the expression of a range of truncated LRP protein fragments, thereby greatly limiting the CEST sensitivity. Here we report the use of a redesigned LRP reporter (rdLRP), aimed to provide excellent stability and CEST sensitivity. The rdLRP contains no DNA repeats or GC rich regions and 30% less positively charged amino-acids. RT-PCR of cell lysates transfected with rdLRP demonstrated a stable reporter gene with a single distinct band corresponding to full-length DNA. A distinct increase in CEST-MRI contrast was obtained in cell lysates of rdLRP transfected cells and in in vivo LRP expressing mouse brain tumors (p=0.0275, n=10).

bioengineering↗

bioRxiv2020

AI boosted molecular MRI for apoptosis detection in oncolytic virotherapy

Oncolytic virotherapy is a promising treatment for high mortality cancers1. Non-invasive imaging of the underlying molecular processes is an essential tool for therapy optimization and assessment of viral spread, innate immunity, and therapeutic response2, 3. However, previous methods for imaging oncolytic viruses did not correlate with late viral activity4 or had poor sensitivity and specificity5. Similarly, methods developed to image treatment response, such as apoptosis, proved to be slow, nonspecific, or require the use of radioactive or metal-based contrast agents6-8. To date, no method has been widely adopted for clinical use. We describe here a new method for fast magnetic resonance molecular imaging with quantitative proton chemical-exchange specificity to monitor oncolytic virotherapy treatment response. A deep neural network enabled the computation of quantitative biomarker maps of protein and lipid/macromolecule concentrations as well as intracellular pH in a glioblastoma multiforme mouse brain tumor model. Early detection of apoptotic response to oncolytic virotherapy, characterized by decreased cytosolic pH and protein synthesis, was observed in agreement with histology. Clinical translation was demonstrated in a normal human subject, yielding molecular parameters in good agreement with literature values9. The developed method is directly applicable to a wide range of pathologies, including stroke10, cancer11-13, and neurological disorders14, 15.

biophysics↗