Oncotarget

Research Papers:

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 Tyler, Henry Brem, Drew M. Pardoll and Michael Lim _

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Oncotarget. 2018; 9:20681-20697. https://doi.org/10.18632/oncotarget.25061

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Abstract

Tomas Garzon-Muvdi1, Debebe Theodros1, Andrew S. Luksik1, Russell Maxwell1, Eileen Kim1, Christopher M. Jackson1, Zineb Belcaid1, Sudipto Ganguly2, Betty Tyler1, Henry Brem1, Drew M. Pardoll2 and Michael Lim1

1Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

2Department of Cancer Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Correspondence to:

Michael Lim, email: mlim3@jhmi.edu

Keywords: PD-1; immunotherapy; glioblastoma; dendritic cells; antigen presentation

Received: October 10, 2017     Accepted: March 21, 2018     Published: April 17, 2018

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.


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