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

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-...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136875/
https://www.ncbi.nlm.nih.gov/pubmed/30221069
http://dx.doi.org/10.1080/2162402X.2018.1466769
Descripción
Sumario: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.