# NKG2D upregulation sensitizes tumors to combined anti-PD1 and anti-VEGF therapy and prevents hearing loss

## TL;DR

Combining anti-PD1 and anti-VEGF therapies effectively treats vestibular schwannomas in mice by improving immune response and preventing hearing loss.

## Contribution

The study demonstrates that NKG2D upregulation enables effective combination therapy for NF2-related schwannomatosis.

## Key findings

- Combination therapy inhibits tumor growth and prevents hearing loss in mouse models.
- Anti-VEGF therapy enhances anti-PD1 efficacy by normalizing tumor vasculature and promoting immune cell infiltration.
- NKG2D upregulation is critical for T and NK cell cytotoxicity in the treatment response.

## Abstract

NF2-related schwannomatosis (NF2-SWN) is a debilitating condition, characterized by bilateral vestibular schwannomas (VSs) that progressively cause irreversible sensorineural hearing loss. Current management relies on surgery or radiotherapy, while bevacizumab (αVEGF) is used off-label, with variable and often transient efficacy. Effective therapies that durably suppress tumor growth and preserve hearing are urgently needed. Although immune checkpoint inhibitors have transformed cancer treatment, their efficacy in non-malignant tumors such as VS remains unclear. Here, we evaluate combined anti-PD1 (αPD1) and αVEGF therapy in two syngeneic, immune-competent VS models. Combination treatment significantly outperforms either monotherapy, inhibiting tumor growth and preventing hearing loss. Mechanistically, αVEGF enhances αPD1 efficacy by normalizing tumor vasculature, improving drug delivery and immune cell infiltration, and promoting cytotoxicity of T and NK cells via NKG2D upregulation. Combined treatment effectively controls tumor growth that progresses despite anti-VEGF therapy. These findings support αPD1 and αVEGF combination therapy as a promising strategy for NF2-SWN.

Vestibular schwannomas that are caused by genetic mutations in the NF2 gene are hard to treat and lead to hearing loss. Here authors show in a mouse model that faithfully represents the human condition that combination therapy with anti-PD-1 and anti-VEGF inhibits tumor growth via normalizing the tumor vasculature and enhances T and NK cell antitumor cytotoxicity via upregulation of NKG2D.