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

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 ParkHenry Brem, Drew M. Pardoll, Michael Lim

Research output: Contribution to journalArticle

51 Scopus citations

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.

Original languageEnglish (US)
Article numbere1466769
JournalOncoImmunology
Volume7
Issue number8
DOIs
StatePublished - Aug 3 2018
Externally publishedYes

Keywords

  • CD155
  • checkpoint inhibitor
  • dendritic cell
  • GBM
  • glioma
  • immunotherapy
  • PD-1
  • PVR
  • TIGIT

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

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    Hung, A. L., Maxwell, R., Theodros, D., Belcaid, Z., Mathios, D., Luksik, A. S., Kim, E., Wu, A., Xia, Y., Garzon-Muvdi, T., Jackson, C., Ye, X., Tyler, B., Selby, M., Korman, A., Barnhart, B., Park, S. M., Youn, J. I., Chowdhury, T., ... Lim, M. (2018). TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. OncoImmunology, 7(8), [e1466769]. https://doi.org/10.1080/2162402X.2018.1466769