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Tytuł:
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TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM
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Autorzy:
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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
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Źródło:
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OncoImmunology; August 2018, Vol. 7 Issue: 8
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ABSTRACTThe 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.