Our Research
Our lab investigates how brain tumors exploit the CHEK2 pathway to evade the immune system. While traditional immunotherapy often fails in gliomas, our work identifies CHEK2 as a "tumor-intrinsic" checkpoint that actively shields cancer cells from immune attack.
By dissecting the molecular signaling of the CHEK2-YBX1/YBX3 axis and the role of germline mutations, we aim to bridge the gap between basic biology and clinical application. Our goal is to develop biomarker-driven strategies that reprogram the tumor environment, turning immune resistance into therapeutic vulnerability for patients.
Current Projects
CHEK2-YBX1/YBX3 as a Tumor-Intrinsic Immune Checkpoint in Gliomas
We identified CHEK2 as a tumor-intrinsic immune checkpoint that enables gliomas to evade CD8⁺ T-cell–mediated killing. Genetic or pharmacologic inhibition of CHEK2 sensitizes tumors to PD-1/PD-L1 blockade. Ongoing work dissects the CHEK2-YBX1/YBX3 axis and targets YBX1 to enhance antitumor immunity.
View part of this work in Neuro-Oncology
Immune-Stimulatory Effects of CHEK2 Mutations in Brain Tumors
CHEK2 mutations and deletions are prevalent in gliomas and meningiomas and may predict responsiveness to immunotherapy. We are investigating how germline pathogenic CHEK2 variants influence CD8⁺ T-cell function and immune gene signatures in tumors. This work aims to identify biomarker-driven strategies for selecting patients with CHEK2-mutant tumors for immune-based therapies.
Tumor-Intrinsic CHEK2 Regulates Glioma-Associated Myeloid Cells
This project examines how tumor-intrinsic CHEK2 signaling shapes the phenotype and function of glioma-associated macrophages and microglia. Loss of CHEK2 reprograms the tumor microenvironment toward a pro-inflammatory, immune-permissive state. These studies define CHEK2 as a key mediator of tumor-myeloid cell crosstalk.
CHEK2 Haploinsufficiency Drives Immune Responsiveness in Aggressive Meningiomas
We investigate how CHEK2 haploinsufficiency, frequently co-deleted with NF2 in high-grade meningiomas, promotes immune activation. Reduced CHEK2 enhances antigen presentation, STING type I interferon signaling, and lymphocyte activation. This work identifies CHEK2-deficient meningiomas as candidates for immune checkpoint blockade therapy.
Identify and target genetic determinants of immune vulnerabilities in brain malignancies
We hypothesize that macrophage-targeted expression of IFN-γ, delivered via genetically engineered HSCs using hCD68-driven clinically relevant lentiviral vectors, will enable selective and durable immune activation within the glioma TME, thereby enhancing anti-tumor responses.
By developing a macrophage-specific, HSC-based gene delivery platform for sustained cytokine expression within the TME, we aim to establish a new modality for precise and durable immune reprogramming. The successful completion of this funding period will provide proof-of-concept data for a broadly applicable and modular therapeutic strategy that can be adapted for other immunosuppressive malignancies beyond brain malignancies.
Targeting EphA3 to Improve Checkpoint Blockade Response in Glioma
EphA3, a membrane-bound receptor tyrosine kinase, emerged from an in vivo CRISPR screen as a key mediator of glioma resistance to PD‑1 blockade. We are testing the combination of EphA3-targeting strategies with PD‑1 inhibitors in glioma models and profiling immune responses. This approach may uncover new combinatorial strategies to overcome immune resistance in GBM.