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

Autor: Alice L. Hung, Russell Maxwell, Debebe Theodros, Zineb Belcaid, Dimitrios Mathios, Andrew S. Luksik, Eileen Kim, Adela Wu, Yuanxuan Xia, Tomas Garzon-Muvdi, Christopher Jackson, Xiaobu Ye, Betty Tyler, Mark Selby, Alan Korman, Bryan Barnhart, Su-Myeong Park, Je-In Youn, Tamrin Chowdhury, Chul-Kee Park, Henry Brem, Drew M. Pardoll, Michael Lim
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: OncoImmunology, Vol 7, Iss 8 (2018)
Druh dokumentu: article
ISSN: 2162-402X
2162402X
DOI: 10.1080/2162402X.2018.1466769
Popis: 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.
Databáze: Directory of Open Access Journals
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