title: Serum elevation of B lymphocyte stimulator does not increase regulatory B cells in glioblastoma patients undergoing immunotherapy.
abstract: Regulatory B cells that secrete IL-10 (IL-10(+) Bregs) represent a suppressive subset of the B cell compartment with prominent anti-inflammatory capacity, capable of suppressing cellular and humoral responses to cancer and vaccines. B lymphocyte stimulator (BLyS) is a key regulatory molecule in IL-10(+) Breg biology with tightly controlled serum levels. However, BLyS levels can be drastically altered upon chemotherapeutic intervention. We have previously shown that serum BLyS levels are elevated, and directly associated, with increased antigen-specific antibody titers in patients with glioblastoma (GBM) undergoing lymphodepletive temozolomide chemotherapy and vaccination. In this study, we examined corresponding IL-10(+) Breg responses within this patient population and demonstrate that the IL-10(+) Breg compartment remains constant before and after administration of the vaccine, despite elevated BLyS levels in circulation. IL-10(+) Breg frequencies were not associated with serum BLyS levels, and ex vivo stimulation with a physiologically relevant concentration of BLyS did not increase IL-10(+) Breg frequency. However, BLyS stimulation did increase the frequency of the overall B cell compartment and promoted B cell proliferation upon B cell receptor engagement. Therefore, using BLyS as an adjuvant with therapeutic peptide vaccination could promote humoral immunity with no increase in immunosuppressive IL-10(+) Bregs. These results have implications for modulating humoral responses in human peptide vaccine trials in patients with GBM.
authors.affiliation: The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.
authors.forename: Anirudh
authors.initials: A
authors.lastname: Saraswathula
authors.affiliation: Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Box 3050, Durham, NC, 27710, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Reap
authors.affiliation: Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Box 3050, Durham, NC, 27710, USA.|Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Choi
authors.affiliation: Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Box 3050, Durham, NC, 27710, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schmittling
authors.affiliation: Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Box 3050, Durham, NC, 27710, USA.
authors.forename: Pamela K
authors.initials: PK
authors.lastname: Norberg
authors.affiliation: Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Box 3050, Durham, NC, 27710, USA.|Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Elias J
authors.initials: EJ
authors.lastname: Sayour
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Healy
authors.affiliation: Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Box 3050, Durham, NC, 27710, USA.
authors.forename: Kendra L
authors.initials: KL
authors.lastname: Congdon
authors.affiliation: The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.|Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Box 3050, Durham, NC, 27710, USA.
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Archer
authors.affiliation: Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Box 3050, Durham, NC, 27710, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Perez
authors.affiliation: The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. john.sampson@duke.edu.|Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Box 3050, Durham, NC, 27710, USA. john.sampson@duke.edu.|Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, NC, USA. john.sampson@duke.edu.|Department of Pathology, Duke University Medical Center, Durham, NC, USA. john.sampson@duke.edu.
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
mesh_terms: D000906:Antibodies / Q000097:blood / Q000276:immunology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D053264:B-Cell Activating Factor / Q000097:blood*; D060151:B-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology; D005909:Glioblastoma / Q000097:blood* / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016753:Interleukin-10 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D000077204:Temozolomide; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000906:Antibodies; D018906:Antineoplastic Agents, Alkylating; D053264:B-Cell Activating Factor; D019496:Cancer Vaccines; D022223:Vaccines, Subunit; C410723:epidermal growth factor receptor VIII; D016753:Interleukin-10; D003606:Dacarbazine; D066246:ErbB Receptors; D000077204:Temozolomide
keywords: BAFF; BLyS; Bregs; GBM; Immunotherapy; Lymphopenia