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PD-1 blockade enhances the vaccination-induced immune response in glioma
Joseph P. Antonios, … , Linda M. Liau, Robert M. Prins
Joseph P. Antonios, … , Linda M. Liau, Robert M. Prins
Published July 7, 2016
Citation Information: JCI Insight. 2016;1(10):e87059. https://doi.org/10.1172/jci.insight.87059.
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Research Article Immunology Oncology

PD-1 blockade enhances the vaccination-induced immune response in glioma

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Abstract

DC vaccination with autologous tumor lysate has demonstrated promising results for the treatment of glioblastoma (GBM) in preclinical and clinical studies. While the vaccine appears capable of inducing T cell infiltration into tumors, the effectiveness of active vaccination in progressively growing tumors is less profound. In parallel, a number of studies have identified negative costimulatory pathways, such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1), as relevant mediators of the intratumoral immune responses. Clinical responses to PD-1 pathway inhibition, however, have also been varied. To evaluate the relevance to established glioma, the effects of PD-1 blockade following DC vaccination were tested in intracranial (i.c.) glioma tumor–bearing mice. Treatment with both DC vaccination and PD-1 mAb blockade resulted in long-term survival, while neither agent alone induced a survival benefit in animals with larger, established tumors. This survival benefit was completely dependent on CD8+ T cells. Additionally, DC vaccine plus PD-1 mAb blockade resulted in the upregulation of integrin homing and immunologic memory markers on tumor-infiltrating lymphocytes (TILs). In clinical samples, DC vaccination in GBM patients was associated with upregulation of PD-1 expression in vivo, while ex vivo blockade of PD-1 on freshly isolated TILs dramatically enhanced autologous tumor cell cytolysis. These findings strongly suggest that the PD-1/PD-L1 pathway plays an important role in the adaptive immune resistance of established GBM in response to antitumor active vaccination and provide us with a rationale for the clinical translation of this combination therapy.

Authors

Joseph P. Antonios, Horacio Soto, Richard G. Everson, Joey Orpilla, Diana Moughon, Namjo Shin, Shaina Sedighim, William H. Yong, Gang Li, Timothy F. Cloughesy, Linda M. Liau, Robert M. Prins

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Figure 1

DC vaccination promotes an antitumor but ineffective infiltrating immune response in the established setting.

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DC vaccination promotes an antitumor but ineffective infiltrating immune...
Mice intracranially (i.c.) implanted with GL261 were randomly assigned to receive DC vaccine treatments (A) at time of implant (low tumor burden) or (B) once tumors became established (elevated tumor burden). Data shown are representative of 1 experiment repeated 2 times with similar findings. (C–F) IHC staining with anti-CD3 antibody (red) on brains harvested from these mice (×20 magnification). (G) CD3+Thy1.2+ cells were FACS sorted from i.c. GL261 gliomas or spleens and plated with GL261 cells for in vitro xCelligence cytotoxicity assay (n = 3) (****P < 0.0001). Data shown are representative of 1 experiment repeated 2 times with similar findings. Each point represents 1 subject (A and B) or the average of biological replicate (n = 4) (G). Survival differences were calculated using log-rank statistical tests and graphed using the method of Kaplan-Meier (A and B), and a Student’s t test was used to calculate statistical significance at individual time points (G).

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