Research Focus
We seek to understand the tumor immune microenvironment and aim to develop novel immunotherapy for meningiomas. Positioned at the crossroads of neuroscience, neuroimmunology, and neuro-oncology, our work bridges fundamental cancer discovery with translational impact. We were the first to demonstrate the effectiveness of systemic adoptive T cell therapy using engineered TCR-T cells targeting NY-ESO-1 in meningiomas (Journal of Neuro-Oncology, 2025)—a milestone that opens the door to transformative, targeted treatments for patients with these challenging tumors.
Meningioma Epidemiology
Meningiomas are the most common adult primary brain tumors with 170,000 diagnosed in the U.S. every year. A subset (~25%) are clinically aggressive, and recur despite standard of care, consisting of surgery and radiation therapy. The five-year overall survival is below 80% and 50% for grade II and III meningiomas, respectively. There is no FDA approved adjuvant therapy or immunotherapy currently.
The Justification for Meningioma Immunotherapy
Unlike intra-axial brain tumors, meningiomas are not protected by the blood-brain-barrier, and are better candidates for immunotherapy than gliomas. But similar to gliomas, meningiomas also have an immunosuppressive tumor immune microenvironment that correlates with prognosis, with PD-L1+ tumor cells, exhausted T cells and regulatory T cells (Treg). We face two scientific challenges in the development meningioma immunotherapy: 1) the unknown effects of RT on the tumor immune microenvironment; and 2) the lack of candidate immunotherapeutically-
Radiation Therapy Affects the Tumor Immune Microenvironment (TIM) and Immunotherapy Efficacy
RT can promote immunoresistance in TIM, thus hinder immunotherapeutic efforts. For example, RT can upregulate immune checkpoint molecules (ICM) via activation of the cGAS-STING pathway through NF-kB and IRF3, promotes regulatory T cells (Treg), and induce T cell exhaustion in TIM. Additionally, RT induces the remaining tumor cells to produce elevated CCL2, CCL5 and CXCL12 that recruit immunosuppressive macrophages (M2) and upregulation of PD-L1 in them. Consequently, in the most recent immunotherapy clinical trials systemic cancers, RT is increasingly combined with immune checkpoint inhibitors (ICI) and other targeted immunotherapies12 to improve survival in various cancers, including head and neck carcinomas.
NY-ESO-1 as a Therapeutic Target for Meningioma Immunotherapy
NY-ESO-1 (gene name: CTAB1B) belongs to the cancer testis antigen (CTA) family of proteins that are only expressed in certain cancer and germ cells but are not expressed in normal somatic cells. Because of this unique property, CTAs can be ideal targets for cancer immunotherapy. Clinical trials targeting NY-ESO-1 using T cells expressing engineered T cell receptor (TCR-T) to treat metastatic solid cancers demonstrated promising clinical efficacy with minimal toxicity, but it has not been clinically tested yet in meningiomas.
PD-L1/PD-1 as a Target to Overcome Immunosuppression in Meningiomas
PD-L1 is a ligand that binds to PD-1 on the surface of T cells and causes T cell dysfunction, exhaustion, and neutralization. It therefore plays a major role in immunosuppression in many systemic cancers as well as for glioblastomas. PD-L1 overexpression in many cancers is not only an important biomarker that predicts survival outcome, but also response to immunotherapy. However, its biological role in meningioma is less well understood. Evidence suggests that over 50% of grade II and III meningiomas overexpress PD-L1, with higher expression found in higher grade tumors. Both tumor and peripheral monocytes in meningiomas have been found to have PD-L1 expression. Clinical studies found that PD-L1 expression in meningioma tumor cells, but not tumor-infiltrating macrophages, was an independent predictor of worse overall survival when accounting for grade, performance status, extent of resection, and recurrence history.
The meningioma tumor microenvironment is relatively understudied compared to glioblastoma, but recent evidence points to a potentially immunosuppressive microenvironment that’s associated with PD-L1/PD-1 expression. For example, the majority of tumor infiltrating T cells in high grade meningiomas were PD-1+ and are either the exhausted T cell phenotype or are T regulatory (Treg) cells that are immunosuppressive, even though higher grade meningiomas may have increased T cell infiltration compared to low grade tumors. Clinical data also suggest that tumor PD-L1 expression, proportion of tumor infiltrating PD1+ T cells, as well as PD-L1+ macrophages are all independent predictors of worse prognosis for meningiomas. Given the clinical significance of the PD-L1/PD-1 pathway, we must seek to understand its biological significance in meningiomas and how to best target it in immunotherapies.