After demonstrating high TIGIT and PD-1 expression on CD4+ and CD8+ cells in brains of glioma patients and confirming these results in a GL261 murine model of glioblastoma, Hung et al. tested TIGIT checkpoint inhibition in combination with anti-PD-1 therapy. Compared to either monotherapy, the combination significantly improved overall survival, elevated TIL CD8+ and CD4+ T cells, and increased the population of IFNγ- and TNFα-producing T cells. Long-term tumor-free murine survivors were immune to rechallenge with GL261-luc cells.
The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.
Author Info: (a) Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, USA; (b) Department of Oncology, Johns Hopkins Hospital, Baltimore, MD, USA; ( c )Bristol-Myers Squibb, New Y
Author Info: (a) Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, USA; (b) Department of Oncology, Johns Hopkins Hospital, Baltimore, MD, USA; ( c )Bristol-Myers Squibb, New York, NY, USA; (d) Wide River Institute of Immunology, Seoul National University College of Medicine, Hongcheon, Korea; (e)Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; (f) Department of Neurosurgery, Seoul National Colege of Medicine, Seoul, Korea.
