Biology subjects

Xiu, B.

Publications and source records attributed to Xiu, B..

3 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↗

bioRxiv2022

Neural responses to movie naturalistic stimuli are related to listening demand in cochlear implant users

There is a weak relationship between clinical and self-reported speech perception outcomes in cochlear implant (CI) listeners. Such poor correspondence may be due to differences in clinical and "real-world" listening environments and stimuli. Speech sounds in the real world are often accompanied by visual cues, background environmental noise and is generally in the context of a connected conversation. The aims of this study were to determine if brain responses to naturalistic speech could index speech perception and listening demand in CI users. Accordingly, we recorded high density EEG while CI users listened/watched a naturalistic stimulus (i.e., the television show, "The Office"). We used continuous EEG to quantify "speech neural tracking" (i.e., TRFs, temporal response functions) to the television show audio track and additionally 8-12 Hz (alpha) brain rhythms commonly related to listening effort. Background noise at three different signal-to-noise ratios (SNRs), +5, +10, and +15 dB were presented to vary the difficulty of following the television show mimicking a natural noisy environment. The task included an additional condition of audio-only (no video). After each condition, participants subjectively rated listening demand and the degree of words and conversations they felt they could understand. Fifteen CI users reported progressively higher degrees of listening demand and less words and conversation with increasing background noise. Listening demand and conversation understanding in the audio-only condition was comparable to that of the highest noise condition (+5 dB). The addition of the background noise reduced the degree of speech neural tracking. Mixed effect modeling showed that listening demand and conversation understanding were correlated to cortical speech tracking such that high demand and low conversation understanding lower associated with lower amplitude TRFs. In the high noise condition, greater listening demand was negatively correlated to parietal alpha power such that higher demand was related to lower alpha power. No significant correlations were observed between TRF/alpha and clinical speech perception scores. These results are similar to previous findings showing little relationship between speech perception and quality of life in CI users. However, the physiological responses to complex natural speech may anticipate aspects of quality-of-life measures such as self-perceived listening demand.

neuroscience↗