TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. (3rd August 2018)

• Record Type: Journal Article
• Authors: Hung, Alice L.; Maxwell, Russell; Theodros, Debebe; Belcaid, Zineb; Mathios, Dimitrios; Luksik, Andrew S.; Kim, Eileen; Wu, Adela; Xia, Yuanxuan; Garzon-Muvdi, Tomas; Jackson, Christopher; Ye, Xiaobu; Tyler, Betty; Selby, Mark; Korman, Alan; Barnhart, Bryan; Park, Su-Myeong; Youn, Je-In; Chowdhury, Tamrin; Park, Chul-Kee; Brem, Henry; Pardoll, Drew M.; Lim, Michael
• Is Part Of: Oncoimmunology. Volume 7:Number 8(2018)
• Publication Date: 2018-08-03
• Subjects: TIGIT -- PVR -- CD155 -- PD-1 -- dendritic cell -- glioma -- checkpoint inhibitor -- immunotherapy -- GBM; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2018.1466769
• Languages: English
• ISSNs: 2162-402X

Abstract

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.