Dendritic cell activation enhances anti-PD-1 mediated immunotherapy against glioblastoma

Tomas Garzon-Muvdi, Debebe Theodros, Andrew S. Luksik, Russell Maxwell, Eileen Kim, Christopher M. Jackson, Zineb Belcaid, Sudipto Ganguly, Betty Mae Tyler, Henry Brem, Andrew Mark Pardoll, Michael Lim

Research output: Contribution to journalArticle

Abstract

Introduction: The glioblastoma (GBM) immune microenvironment is highly suppressive as it targets and hinders multiple components of the immune system. Checkpoint blockade (CB) is being evaluated for GBM patients. However, biomarker analyses suggest that CB monotherapy may be effective only in a small fraction of GBM patients. We hypothesized that activation of antigen presentation would increase the therapeutic response to PD-1 blockade. Results: We show that activating DCs through TLR3 agonists enhances the anti-tumor immune response to CB and increases survival in GBM. Mice treated with TLR3 agonist poly(I:C) and anti-PD-1 demonstrated increased DC activation and increased T cell proliferation in tumor draining lymph nodes. We show that DCs are necessary for the improved anti-tumor immune response. Conclusions: This study suggests that augmenting antigen presentation is an effective multimodal immunotherapy strategy that intensifies anti-tumor responses in GBM. Specifically, these data represent an expanded role for TLR3 agonists as adjuvants to CB. Methods: Using a preclinical model of GBM, we tested the efficacy of combinatorial immunotherapy with anti-PD-1 and TLR3 agonist, poly(I:C). Characterization of the immune response in tumor infiltrating immune cells and in secondary lymphoid organs was performed. Additionally, dendritic cell (DC) depletion experiments were performed.

Original languageEnglish (US)
Pages (from-to)20681-20697
Number of pages17
JournalOncotarget
Volume9
Issue number29
DOIs
StatePublished - Apr 17 2018

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Glioblastoma
Immunotherapy
Dendritic Cells
Antigen Presentation
Neoplasms
Immune System
Biomarkers
Lymph Nodes
Cell Proliferation
T-Lymphocytes
Survival

Keywords

  • Antigen presentation
  • Dendritic cells
  • Glioblastoma
  • Immunotherapy
  • PD-1

ASJC Scopus subject areas

  • Oncology

Cite this

Garzon-Muvdi, T., Theodros, D., Luksik, A. S., Maxwell, R., Kim, E., Jackson, C. M., ... Lim, M. (2018). Dendritic cell activation enhances anti-PD-1 mediated immunotherapy against glioblastoma. Oncotarget, 9(29), 20681-20697. https://doi.org/10.18632/oncotarget.25061

Dendritic cell activation enhances anti-PD-1 mediated immunotherapy against glioblastoma. / Garzon-Muvdi, Tomas; Theodros, Debebe; Luksik, Andrew S.; Maxwell, Russell; Kim, Eileen; Jackson, Christopher M.; Belcaid, Zineb; Ganguly, Sudipto; Tyler, Betty Mae; Brem, Henry; Pardoll, Andrew Mark; Lim, Michael.

In: Oncotarget, Vol. 9, No. 29, 17.04.2018, p. 20681-20697.

Research output: Contribution to journalArticle

Garzon-Muvdi, T, Theodros, D, Luksik, AS, Maxwell, R, Kim, E, Jackson, CM, Belcaid, Z, Ganguly, S, Tyler, BM, Brem, H, Pardoll, AM & Lim, M 2018, 'Dendritic cell activation enhances anti-PD-1 mediated immunotherapy against glioblastoma', Oncotarget, vol. 9, no. 29, pp. 20681-20697. https://doi.org/10.18632/oncotarget.25061
Garzon-Muvdi T, Theodros D, Luksik AS, Maxwell R, Kim E, Jackson CM et al. Dendritic cell activation enhances anti-PD-1 mediated immunotherapy against glioblastoma. Oncotarget. 2018 Apr 17;9(29):20681-20697. https://doi.org/10.18632/oncotarget.25061
Garzon-Muvdi, Tomas ; Theodros, Debebe ; Luksik, Andrew S. ; Maxwell, Russell ; Kim, Eileen ; Jackson, Christopher M. ; Belcaid, Zineb ; Ganguly, Sudipto ; Tyler, Betty Mae ; Brem, Henry ; Pardoll, Andrew Mark ; Lim, Michael. / Dendritic cell activation enhances anti-PD-1 mediated immunotherapy against glioblastoma. In: Oncotarget. 2018 ; Vol. 9, No. 29. pp. 20681-20697.
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