Abstract
IntroductionThe 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.ResultsWe 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.ConclusionsThis 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.MethodsUsing 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.
Highlights
The glioblastoma (GBM) immune microenvironment is highly suppressive as it targets and hinders multiple components of the immune system
Mice treated with TLR3 agonist poly(I:C) and anti-Programmed Cell Death 1 (PD-1) demonstrated increased dendritic cell (DC) activation and increased T cell proliferation in tumor draining lymph nodes
This study suggests that augmenting antigen presentation is an effective multimodal immunotherapy strategy that intensifies anti-tumor responses in GBM
Summary
The glioblastoma (GBM) immune microenvironment is highly suppressive as it targets and hinders multiple components of the immune system. 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. Immune checkpoint blockade (CB) has yielded durable responses in multiple tumor types and immune checkpoint blocking antibodies are being actively investigated in GBM. Checkpoint molecules are high jacked by tumors to evade the immune surveillance. Antibodies targeting these molecules have recently been approved by the Food and Drug Administration (FDA) for the treatment of multiple cancers [5]. Comprehensive biomarker analyses suggest that CB monotherapy may be effective only in a small subset of GBM patients [11]
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