Garzon-Muvdi et al. treated mice bearing orthotopic glioma with the TLR3 agonist poly(I:C) alone or in combination with anti-PD-1. Poly(I:C) enhanced the activation of resident DCs in the brain as well as migratory DCs in the deep cervical lymph nodes, and combination treatment with anti-PD-1 increased the percentage of IFNγ-producing effector CD8+ T cells in the brain. Cumulatively, this led to increased survival and establishment of memory response. Treatment increased PD-L1 expression on myeloid cells in the brain, spleen, and lymph nodes, though this did not negatively impact survival.
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.
Author Info: (1) Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (2) Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltim
Author Info: (1) Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (2) Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (3) Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (4) Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (5) Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (6) Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (7) Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (8) Department of Cancer Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (9) Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (10) Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (11) Department of Cancer Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (12) Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
