title: Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM.
abstract: The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immune response. We show that LC combined with anti-programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8+cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo- and immunotherapy had differential effects on anti-PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti-PD-1. The results of this work could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types.
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mathios
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Antonella
authors.initials: A
authors.lastname: Mangraviti
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Jillian
authors.initials: J
authors.lastname: Phallen
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-744, South Korea.
authors.forename: Chul-Kee
authors.initials: CK
authors.lastname: Park
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Jackson
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Garzon-Muvdi
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Debebe
authors.initials: D
authors.lastname: Theodros
authors.affiliation: Department of Cancer Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Polanczyk
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Martin
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Suk
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Xiaobu
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Tyler
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Chetan
authors.initials: C
authors.lastname: Bettegowda
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
authors.affiliation: Department of Cancer Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. mlim3@jhmi.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Lim
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002330:Carmustine / Q000494:pharmacology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy*; D005910:Glioma / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D002330:Carmustine