TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

Area of Science:

• Immunology
• Oncology
• Neuro-oncology

Background:

• Immune checkpoint inhibitors (ICIs) are explored for glioblastoma (GBM) treatment.
• TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a novel immune checkpoint target.
• Understanding TIGIT's role in GBM immunity is crucial for therapeutic development.

Purpose of the Study:

• To evaluate the efficacy of combined anti-PD-1 and anti-TIGIT therapy in a murine GBM model.
• To investigate the immunological mechanisms underlying the combination therapy's effects.
• To assess the clinical relevance of TIGIT in human GBM.

Main Methods:

• Utilized a murine intracranial GL261-luc+ glioblastoma model.
• Administered anti-PD-1 and anti-TIGIT monotherapy and combination therapy.
• Analyzed T cell populations (CD8+, Tregs) and tumor-infiltrating dendritic cells (TIDCs) in brain, lymph nodes, and spleen.
• Correlated therapeutic effects with immune cell function and patient data.

Main Results:

• TIGIT expression was upregulated on T cells and Tregs within the brain tumors.
• Dual anti-PD-1/anti-TIGIT therapy significantly improved survival compared to control and monotherapy.
• Therapeutic benefits were associated with enhanced effector T cell activity and reduced suppressive Tregs and TIDCs.
• Elevated TIGIT expression was observed in human GBM tumor-infiltrating lymphocytes, and PVR expression correlated with poor prognosis in low-grade glioma.

Conclusions:

• Combination therapy targeting PD-1 and TIGIT demonstrates significant survival benefits in a preclinical GBM model.
• The combination therapy modulates both T cell and myeloid compartments, reducing tumor-induced immunosuppression.
• TIGIT represents a promising therapeutic target for glioblastoma, supported by its expression in human GBM and correlation with patient outcomes.