A Novel Therapeutic Approach: Gamma Secretase Inhibitor Enhances Radiotherapy and Checkpoint Blockade Therapy via...

Area of Science:

• Oncology
• Immunology
• Cancer Research

Background:

• High-dose radiotherapy (RT) is immunogenic but creates an immunosuppressive tumor microenvironment (TME) limiting immune checkpoint inhibitor (ICI) efficacy.
• Notch signaling influences the TME, suggesting its inhibition could counteract radiation-induced immunosuppression.
• Overcoming the immunosuppressive TME is crucial for enhancing RT-ICI combination therapies.

Purpose of the Study:

• To investigate if a gamma-secretase inhibitor (GSI), AL101, can suppress radiation-induced immunosuppression.
• To evaluate the potential of combining GSI with RT and anti-PD-1 (aPD-1) therapy to enhance anti-tumor efficacy.

Main Methods:

• Syngeneic neuroblastoma and triple-negative breast cancer models were used in mice.
• Mice received RT, AL101 (GSI), and aPD-1 therapy in combination.
• Tumor immune microenvironment was analyzed using spectral flow cytometry and single-cell RNA sequencing (scRNA-seq).

Main Results:

• The triple combination of RT, aPD-1, and GSI significantly inhibited tumor growth and more than doubled median survival.
• This combination therapy reduced lung metastases and was dependent on an intact immune system and macrophages.
• scRNA-seq and flow cytometry revealed that triple therapy expanded CD8+ T cells, reduced Tregs, restored dendritic cells, and shifted myeloid cells to a proinflammatory state, reversing RT-induced exhaustion and immunosuppression.

Conclusions:

• Gamma-secretase inhibitor (GSI) effectively remodels the RT-induced immunosuppressive TME.
• GSI potentiates the efficacy of RT plus ICI therapy by reprogramming the TME towards an immunostimulatory state.
• GSI represents a promising immuno-radiotherapeutic strategy with significant translational potential for cancer treatment.