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

Abstract

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.

TIGIT as an emerging immune checkpoint

“…In this last study, even though single therapies increased CD8 + T cell IFN‐γ production in the tumour‐infiltrating lymph node, only TIGIT/PD‐L1 co‐blockade significantly increased CD8 + T cell IFN‐γ production in the tumour. Further supporting the potent anti‐tumour effect of TIGIT/PD‐1 co‐blockade, two groups have shown that this combination therapy protected mice against orthotopically implanted GL261 glioblastoma . Finally, co‐blockade of TIGIT and PD‐L1 in combination with radiotherapy resulted in 90% cure rates of mice bearing CT26 subcutaneous tumours .…”

Differential Expression of the T cell Inhibitor TIGIT in Glioblastoma and Multiple Sclerosis

“…Here we report that TIGIT expressing lymphocytes were substantially higher in glioblastoma infiltrates than in MS lesions. Previous studies have reported similar frequencies of TIGIT + tumorinfiltrating lymphocytes in glioblastoma (25%-60%), although they have not been able to address whether those frequencies represent the level of TIGIT T cell expression in any CNS environment or a feature specific to the glioblastoma infiltrate [20,26]. Given the abundant expression of the TIGIT ligand, CD155, on glioblastoma cells, this suggests that TIGIT signaling critically limits antitumor responses in GBM.…”

“…Indeed, increased TIGIT has been demonstrated on tumor-infiltrating lymphocytes in a number of cancers including non-small cell lung cancer (NSCLC) and melanoma [15,18]. Moreover, TIGIT blockade in animal models and in CD4 and CD8 T cells isolated from human tumors showed reinvigoration of anti-tumor immune responses [15,19,20]. However, TIGIT blockade also has the potential for inducing autoimmune disease, as expression of the competing costimulatory receptor, CD226, is increased on peripheral T cells of patients with rheumatoid arthritis and lupus [21].…”

Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner

“…Immunotherapy options remain limited for GBM, despite the success of these treatment modalities in pre-clinical models and other solid tumors [31][32][33][34] . The immunosuppressive tumor microenvironment mainly consisting of myeloid cells is one of the major factors limiting the efficacy of existing treatment options 9 .…”