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NKG2D Upregulation Enhances T and NK Cell Cytotoxicity, Sensitizes Tumors to Combined αPD1 and αVEGF Therapy, and Contributes to Hearing Loss Prevention in Vestibular Schwannoma Model

ABSTRACT: Background: NF2-related schwannomatosis (NF2-SWN) is a debilitating condition that calls for robust treatment options. NF2-SWN is characterized by 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 monoclonal antibody (αVEGF), has been 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 VS growth and associated hearing loss. While immune checkpoint inhibitors have transformed cancer therapy, their potential has not been thoroughly explored in non-malignant tumors such as VS. Methods: We characterize the effects of combined anti-programmed cell death protein-1 (αPD1) and αVEGF treatment on tumor growth and hearing function in two syngeneic, immune-competent VS models. Results: Combining αVEGF with αPD1 treatment significantly enhances the antitumor efficacy of each monotherapy. Specifically, i) αVEGF augments αPD1 efficacy by normalizing tumor vasculature to improve drug delivery and immune cell infiltration, and by activating the antitumor cytotoxicity of T and NK cells via NKG2D upregulation; and ii) combined αPD1 with αVEGF treatment effectively controls the growth of tumors that progressed despite αVEGF treatment. Conclusion: These findings provide a strong foundation for the αPD1 with αVEGF combination therapies to treat patients with NF2-SWN.

ORGANISM(S): Homo sapiens

PROVIDER: GSE315579 | GEO | 2026/01/09

REPOSITORIES: GEO

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Project description:Object: The main limitation of treatment strategies for vestibular schwannomas (VSs) is loss of function of vestibulocochlear and facial nerves, which has driven investigations into new pharmaceutical therapies. The most common genetic alteration in human VSs is loss ofthe NF2 gene which encodes the protein merlin. It is well established that merlin achieves tumor suppressive functions through regulation of the Hippo pathway. The aim of this study was to analyze dysregulation of the Hippo pathway in sporadic VSs and to identify whether Hippo signaling could be potential targetable pathway for treatment of VS. Methods: In this study, we performed gene expression profiling of ten human sporadic VSs and four normal control vestibular nerves to identify aberrant expression of the Hippo pathway in VSs. Molecular subtypes in VSs was evaluated using unsupervised hierarchical clustering analysis. Western blot analysis and immunohistochemical staining were used to examine the expression of Hippo pathway core components in twenty human sporadic VSs. NF2 gene sequencing and mutation analysis were performed in all VS samples. Ki67 marker was used to investigate proliferation of tumor cells. Verteporfin was used to determine whether the inhibitor of YAP-TEAD reduced proliferation of human primary VS cells with NF2 mutations and RT4-D6P2T cell line. Results: We found fifty-one differentially expressed genes between VSs and controls. Unsupervised analysis of transcriptional profiles identified the two distinct molecular variants, which was significantly associated with NF2 mutation status. The protein level of MST2, LAST2,phospho-LAST1, and phospho-YAP were significantly decreased in VSs compared with normal tissues. Nuclear YAP staining was positively correlated with Ki-67 indexin VS samples. Finally, verteporfin reduced viability of human primary VS cells and in a dose-dependent manner by decreasing YAP expression. Conclusions: Our findings implicate that deregulation of the Hippo pathway as a molecular mechanism of pathogenesis in human sporadic VSs, and suggest inhibition of this pathway as a potential treatment strategy.

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NKG2D Upregulation Enhances T and NK Cell Cytotoxicity, Sensitizes Tumors to Combined αPD1 and αVEGF Therapy, and Contributes to Hearing Loss Prevention in Vestibular Schwannoma Model

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