title: PD-1 blockade enhances the vaccination-induced immune response in glioma.
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.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Antonios
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA.
authors.forename: Horacio
authors.initials: H
authors.lastname: Soto
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Everson
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA.
authors.forename: Joey
authors.initials: J
authors.lastname: Orpilla
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Moughon
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA.
authors.forename: Namjo
authors.initials: N
authors.lastname: Shin
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA.
authors.forename: Shaina
authors.initials: S
authors.lastname: Sedighim
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.affiliation: Department of Biostatistics, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Brain Research Institute, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA; Jonsson Comprehensive Cancer Center (JCCC), David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA; Department of Neurology, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA; Brain Research Institute, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA; Jonsson Comprehensive Cancer Center (JCCC), David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Liau
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA; Brain Research Institute, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA; Jonsson Comprehensive Cancer Center (JCCC), David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Prins