Biology subjects

Jones, A. P.

Publications and source records attributed to Jones, A. P..

6 recordsLinked to original sources

bioRxiv2024

Direct and abscopal anti-tumor responses elicited by peripheral nerve schwannoma irradiation synergize with anti-PD1 treatment in vestibular schwannoma models

NF2-related schwannomatosis (NF2-SWN) is a progressive and disabling disease requiring effective treatments. The hallmark of NF2-SWN is bilateral vestibular schwannomas (VSs), which progressively enlarge, leading to permanent sensorineural hearing loss and severely impacting patients quality of life. Currently, there are no FDA-approved drugs for VS or the associated hearing loss. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but have not yet been systematically investigated in non-malignant tumors such as VS. In our studies, we demonstrated that combining anti-PD1 (PD1) treatment with radiation therapy (RT) provides three significant therapeutic benefits: i) Enhanced PD1 efficacy and immune memory: RT induces immunogenic cell death and activates the STING pathway, enhancing PD1 efficacy and generating long-term immune memory, ii) Reduced RT dose and associated tissue injury: The combination strategy reduces the required RT dose necessary for effective tumor control, potentially minimizing RT injury to surrounding normal tissues, and iii) Elicited abscopal effects on cerebellopontine angle (CPA) schwannomas: RT to peripheral nerve tumor induces a systemic abscopal effect, which synergizes with PD-1 to effectively control intracranial schwannomas without direct irradiation, sparing the cochlea from radiation exposure and avoiding auditory radiation injury. Together, our findings provide a compelling rationale for deploying ICIs in combination with radiotherapy as a novel treatment approach for patients with VS and NF2-SWN.

cancer biology↗

bioRxiv2024

Enhanced Tumor Control and Hearing Loss Prevention Achieved with Combined Immune Checkpoint Inhibitor and Anti-VEGF Therapy in Vestibular Schwannoma Model

BackgroundNF2-related schwannomatosis (NF2-SWN) is a debilitating condition that calls for robust treatment options. The defining feature of NF2-SWN is the presence of bilateral vestibular schwannomas (VSs), which grow over time and can result in irreversible sensorineural hearing loss, significantly affecting the quality of life for those affected. At present, there are no FDA-approved medications specifically for treating VS or related hearing loss. VS management involves radiotherapy or surgical resection, while bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (VEGF) may be used off-label in NF2-SWN to shrink the tumor. However, not all patients respond, and the effect is not always durable. There is a critical need for effective medications that can stop the growth of VS and prevent hearing loss associated with these tumors. While immune checkpoint inhibitors have transformed cancer therapy, their potential has not been thoroughly explored in non-malignant tumors such as VS. MethodsWe characterize the effects of anti-PD1 (PD1) treatment on tumor growth and hearing function in two syngeneic, immune-competent VS models. ResultsWe demonstrated that combining VEGF treatment with PD1 significantly enhances the efficacy of each monotherapy. Specifically, i) VEGF enhances PD1 efficacy by normalizing the tumor vasculature to improve drug delivery and immune cell infiltration, and by activating T cell and NK cell anti-tumor cytotoxicity via NKG2D upregulation; and ii) combining PD1 with VEGF treatment effectively controls tumors that progressed despite VEGF treatment. ConclusionThese findings provide a strong foundation for the development of PD1 with VEGF combination therapies for patients with NF2-SWN. Key pointsWe filled a critical gap in NF2 research: 1) we characterized the effects of immunotherapy on tumor growth and hearing function in non-malignant vestibular schwannomas 2) We showed combined anti-VEGF and anti-PD1 enhances the efficacy of each monotherapy Importance of the studyTreatment options for patients with NF2-SWN are limited or are associated with significant co-morbidities. There are no approved medical treatments for NF2-related tumors. While immune checkpoint inhibitors have transformed cancer therapy, their potential has not been thoroughly explored in non-malignant tumors such as VS. Our work filled this critical gap in NF2-SWN research. For the first time, we systemically evaluated ICI efficacy on tumor growth and hearing function in non-malignant schwannomas. Furthermore, we demonstrated that combining VEGF treatment with PD1 significantly enhances the efficacy of each monotherapy. Specifically: i) VEGF enhances PD1 efficacy by normalizing the tumor vasculature to improve drug delivery and immune cell infiltration, and by activating T cell and NK cell anti-tumor cytotoxicity via NKG2D upregulation; and ii) combining PD1 with VEGF treatment effectively controls tumors that progress despite VEGF treatment. Our findings provide a strong foundation for the development of PD1 with VEGF combination therapies for patients with NF2-SWN.

cancer biology↗

bioRxiv2024

High-Dimensional Imaging of Vestibular Schwannoma Reveals Distinctive Immunological Networks Across Histomorphic Niches in NF2-related Schwannomatosis

NF2-related Schwannomatosis (NF2 SWN) is a rare tumour-predisposition syndrome characterised by the growth of multiple central and peripheral nervous system neoplasms. The drivers of NF2 SWN are pathogenic variants in the tumour suppressor gene NF2, encoding the protein Merlin, leading to development of bilateral vestibular schwannoma (VS) in >95% of patients. VS tumours are characterised by infiltration of myeloid cells and lymphocytes, highlighting the potential of immunotherapy for VS. However, the immunological landscape in VS and the spatial determinants within the tumour microenvironment that shape the trajectory of disease are presently unknown. In this study, to elucidate the complex immunological networks across VS, we performed imaging mass cytometry (IMC) on clinically annotated VS samples from NF2 SWN patients. We reveal the heterogeneity in neoplastic cell, myeloid cell and T cell populations that co-exist within VS, determining that the cellular composition of VS tumours is independent of NF2-SWN genetic severity. We show that distinct myeloid cell and Schwann cell populations exist within varied spatial contextures across characteristic Antoni A and B histomorphic niches. Interestingly, we show that T-cell populations associate with tumour-associated macrophages (TAMs) in Antoni A regions, seemingly limiting their ability to interact with tumorigenic Schwann cells. This spatial landscape is altered in Antoni B regions, where T-cell populations appear to interact with PD-L1+ Schwann cells. We also demonstrate that prior bevacizumab treatment (VEGF-A antagonist) preferentially reduces alternatively-activated TAMs, whilst enhancing CD44 expression, in bevacizumab-treated tumours. Together, we describe niche-dependent modes of T-cell regulation in NF2 SWN VS, indicating the potential for microenvironment-altering therapies for VS. TeaserImaging mass cytometry and spatial omic analyses illustrate spatially-distinct regions of T-cell regulation in vestibular schwannoma.

immunology↗

bioRxiv2020

The acute effects of cannabidiol on emotional processing and anxiety: a neurocognitive imaging study

BackgroundThere is growing interest in the therapeutic potential of cannabidiol (CBD) across a range of psychiatric disorders. CBD has been found to reduce anxiety during experimentally-induced stress in anxious individuals and healthy controls. However, the mechanisms underlying the putative anxiolytic effects of CBD are unknown. We therefore sought to investigate the behavioural and neural effects of a single dose of CBD vs. placebo on a range of emotion-related measures to test cognitive-mechanistic models of its effects on anxiety. MethodsWe conducted a randomised, double-blind, placebo-controlled, crossover, acute oral challenge of 600 mg of CBD in 24 healthy participants on emotional processing, with neuroimaging (viewing emotional faces during fMRI) and cognitive (emotional appraisal) measures as well as subjective response to experimentally-induced anxiety. ResultsCBD did not produce effects on BOLD responses to emotional faces, cognitive measures of emotional processing, or modulate experimentally-induced anxiety, relative to placebo. ConclusionsGiven the rising popularity of CBD for its putative medical benefits, further research is warranted to investigate the clinical potential of CBD for the treatment of anxiety disorders.

neuroscience↗

bioRxiv2019

Delayed suppression normalizes face identity responses in the primate brain

SummaryThe primate brain is specialized for social visual perception. Previous work indicates that recognition draws upon an internal comparison between a viewed face and an internally stored average face. Here we demonstrate that this comparison takes the form of a delayed, dynamic suppression of face averageness among single neurons. In three macaque face patches, spiking responses to low-identity morphed faces met with a synchronous attenuation starting approximately 200 ms after onset. Analysis showed that a late-emerging V-shaped identity tuning was sometimes superimposed on linear ramp tuning. This pattern could not be ascribed to repetition suppression within a given session. The results indicate that the brains analysis of faces is enhanced through predictive normalization of identity, which increases sensitivity among face-selective neurons to distinctive facial features known to drive recognition.

neuroscience↗

bioRxiv2019

Spatiotemporal patterns of transcranial electrical stimulation can strengthen the metamemory of individual episodic memories in humans

Targeted memory reactivation (TMR) during slow-wave oscillations (SWOs) in non-rapid eye movement (NREM) sleep has been demonstrated with sensory cues to achieve about 5-12% improvement in post-nap memory performance on simple laboratory tasks. But prior work has neither addressed the one-shot aspect of episodic memory acquisition, nor dealt with the presence of interference from ambient environmental cues in real-world settings for the sensory cues. Moreover, TMR with sensory cues may not be scalable to the multitude of experiences over ones lifetime. We designed a novel non-invasive paradigm that tags one-shot experiences of minute-long naturalistic episodes within immersive virtual reality (VR) with unique spatiotemporal amplitude-modulated patterns (STAMPs) of transcranial electrical stimulation (tES) and cues them during SWOs. In particular, we demonstrate that these STAMPs can be re-applied as brief pulses to temporally coincide with UP states of SWOs (0.4167 - 1 s) on two consecutive nights to achieve about 20% improvement in the metamemory of targeted episodes at 48 hours after the one-shot viewing, compared to the control episodes. Post-sleep metamemory of the targeted episodes was driven by an interaction between their pre-sleep metamemory and the number of STAMP applications for those episodes during sleep. Overnight metamemory improvements were mediated by spectral power increases from 6.18 to 6.7 s following the offset of STAMPs in the slow-spindle band (9-12 Hz) for left temporal areas in the scalp electroencephalography (EEG) during sleep. These results prescribe an optimal strategy to leverage STAMPs for boosting metamemory and suggest that real-world episodic memories can be modulated in a targeted manner even with coarser, non-invasive spatiotemporal stimulation.

neuroscience↗