Oncolytic virotherapy in glioblastoma patients induces a tumor macrophage phenotypic shift leading to an altered glioblastoma microenvironment

Wouter B. L. van den Bossche, Anne Kleijn, Charlotte E. Teunissen, Jane S. A. Voerman, Cristina Teodosio, David P. Noske, Jacques J. M. van Dongen, Clemens M. F. Dirven, Martine L. M. Lamfers

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background. Immunosuppressive protumoral M2 macrophages are important in pathogenesis, progression, and therapy resistance in glioblastoma (GBM) and provide a target for therapy. Recently oncolytic virotherapy in murine models was shown to change these M2 macrophages toward the pro-inflammatory and antitumoral M1 phenotype. Here we study the effects of the oncolytic virotherapy Delta24-RGD in humans, using both in vitro models and patient material. Methods. Human monocyte-derived macrophages were co-cultured with Delta24-RGD-infected primary glioma stem-like cells (GSCs) and were analyzed for their immunophenotype, cytokine expression, and secretion profiles. Cerebrospinal fluid (CSF) from 18 Delta24-RGD-treated patients was analyzed for inflammatory cytokine levels, and the effects of these CSF samples on macrophage phenotype in vitro were determined. In addition, tumor macrophages in resected material from a Delta24-RGD-treated GBM patient were compared with 5 control GBM patient samples by flow cytometry. Results. Human monocyte-derived M2 macrophages co-cultured with Delta24-RGD-infected GSCs shifted toward an M1-immunophenotype, coinciding with pro-inflammatory gene expression and cytokine production. This phenotypic switch was induced by the concerted effects of a change in tumor-produced soluble factors and the presence of viral particles. CSF samples from Delta24-RGD-treated GBM patients revealed cytokine levels indicative of a pro-inflammatory microenvironment. Furthermore, tumoral macrophages in a Delta24-RGD-treated patient showed significantly greater M1 characteristics than in control GBM tissue. Conclusion. Together these in vitro and patient studies demonstrate that local Delta24-RGD therapy may provide a therapeutic tool to promote a prolonged shift in the protumoral M2 macrophages toward M1 in human GBM, inducing a pro-inflammatory and potentially tumor-detrimental microenvironment.
Original languageEnglish
Pages (from-to)1494-1504
JournalNeuro-Oncology
Volume20
Issue number11
DOIs
Publication statusPublished - 2018

Cite this

van den Bossche, Wouter B. L. ; Kleijn, Anne ; Teunissen, Charlotte E. ; Voerman, Jane S. A. ; Teodosio, Cristina ; Noske, David P. ; van Dongen, Jacques J. M. ; Dirven, Clemens M. F. ; Lamfers, Martine L. M. / Oncolytic virotherapy in glioblastoma patients induces a tumor macrophage phenotypic shift leading to an altered glioblastoma microenvironment. In: Neuro-Oncology. 2018 ; Vol. 20, No. 11. pp. 1494-1504.
@article{92bf3ba734514a5cae127938bfbf4bb4,
title = "Oncolytic virotherapy in glioblastoma patients induces a tumor macrophage phenotypic shift leading to an altered glioblastoma microenvironment",
abstract = "Background. Immunosuppressive protumoral M2 macrophages are important in pathogenesis, progression, and therapy resistance in glioblastoma (GBM) and provide a target for therapy. Recently oncolytic virotherapy in murine models was shown to change these M2 macrophages toward the pro-inflammatory and antitumoral M1 phenotype. Here we study the effects of the oncolytic virotherapy Delta24-RGD in humans, using both in vitro models and patient material. Methods. Human monocyte-derived macrophages were co-cultured with Delta24-RGD-infected primary glioma stem-like cells (GSCs) and were analyzed for their immunophenotype, cytokine expression, and secretion profiles. Cerebrospinal fluid (CSF) from 18 Delta24-RGD-treated patients was analyzed for inflammatory cytokine levels, and the effects of these CSF samples on macrophage phenotype in vitro were determined. In addition, tumor macrophages in resected material from a Delta24-RGD-treated GBM patient were compared with 5 control GBM patient samples by flow cytometry. Results. Human monocyte-derived M2 macrophages co-cultured with Delta24-RGD-infected GSCs shifted toward an M1-immunophenotype, coinciding with pro-inflammatory gene expression and cytokine production. This phenotypic switch was induced by the concerted effects of a change in tumor-produced soluble factors and the presence of viral particles. CSF samples from Delta24-RGD-treated GBM patients revealed cytokine levels indicative of a pro-inflammatory microenvironment. Furthermore, tumoral macrophages in a Delta24-RGD-treated patient showed significantly greater M1 characteristics than in control GBM tissue. Conclusion. Together these in vitro and patient studies demonstrate that local Delta24-RGD therapy may provide a therapeutic tool to promote a prolonged shift in the protumoral M2 macrophages toward M1 in human GBM, inducing a pro-inflammatory and potentially tumor-detrimental microenvironment.",
author = "{van den Bossche}, {Wouter B. L.} and Anne Kleijn and Teunissen, {Charlotte E.} and Voerman, {Jane S. A.} and Cristina Teodosio and Noske, {David P.} and {van Dongen}, {Jacques J. M.} and Dirven, {Clemens M. F.} and Lamfers, {Martine L. M.}",
year = "2018",
doi = "10.1093/neuonc/noy082",
language = "English",
volume = "20",
pages = "1494--1504",
journal = "Neuro-Oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "11",

}

van den Bossche, WBL, Kleijn, A, Teunissen, CE, Voerman, JSA, Teodosio, C, Noske, DP, van Dongen, JJM, Dirven, CMF & Lamfers, MLM 2018, 'Oncolytic virotherapy in glioblastoma patients induces a tumor macrophage phenotypic shift leading to an altered glioblastoma microenvironment' Neuro-Oncology, vol. 20, no. 11, pp. 1494-1504. https://doi.org/10.1093/neuonc/noy082

Oncolytic virotherapy in glioblastoma patients induces a tumor macrophage phenotypic shift leading to an altered glioblastoma microenvironment. / van den Bossche, Wouter B. L.; Kleijn, Anne; Teunissen, Charlotte E.; Voerman, Jane S. A.; Teodosio, Cristina; Noske, David P.; van Dongen, Jacques J. M.; Dirven, Clemens M. F.; Lamfers, Martine L. M.

In: Neuro-Oncology, Vol. 20, No. 11, 2018, p. 1494-1504.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Oncolytic virotherapy in glioblastoma patients induces a tumor macrophage phenotypic shift leading to an altered glioblastoma microenvironment

AU - van den Bossche, Wouter B. L.

AU - Kleijn, Anne

AU - Teunissen, Charlotte E.

AU - Voerman, Jane S. A.

AU - Teodosio, Cristina

AU - Noske, David P.

AU - van Dongen, Jacques J. M.

AU - Dirven, Clemens M. F.

AU - Lamfers, Martine L. M.

PY - 2018

Y1 - 2018

N2 - Background. Immunosuppressive protumoral M2 macrophages are important in pathogenesis, progression, and therapy resistance in glioblastoma (GBM) and provide a target for therapy. Recently oncolytic virotherapy in murine models was shown to change these M2 macrophages toward the pro-inflammatory and antitumoral M1 phenotype. Here we study the effects of the oncolytic virotherapy Delta24-RGD in humans, using both in vitro models and patient material. Methods. Human monocyte-derived macrophages were co-cultured with Delta24-RGD-infected primary glioma stem-like cells (GSCs) and were analyzed for their immunophenotype, cytokine expression, and secretion profiles. Cerebrospinal fluid (CSF) from 18 Delta24-RGD-treated patients was analyzed for inflammatory cytokine levels, and the effects of these CSF samples on macrophage phenotype in vitro were determined. In addition, tumor macrophages in resected material from a Delta24-RGD-treated GBM patient were compared with 5 control GBM patient samples by flow cytometry. Results. Human monocyte-derived M2 macrophages co-cultured with Delta24-RGD-infected GSCs shifted toward an M1-immunophenotype, coinciding with pro-inflammatory gene expression and cytokine production. This phenotypic switch was induced by the concerted effects of a change in tumor-produced soluble factors and the presence of viral particles. CSF samples from Delta24-RGD-treated GBM patients revealed cytokine levels indicative of a pro-inflammatory microenvironment. Furthermore, tumoral macrophages in a Delta24-RGD-treated patient showed significantly greater M1 characteristics than in control GBM tissue. Conclusion. Together these in vitro and patient studies demonstrate that local Delta24-RGD therapy may provide a therapeutic tool to promote a prolonged shift in the protumoral M2 macrophages toward M1 in human GBM, inducing a pro-inflammatory and potentially tumor-detrimental microenvironment.

AB - Background. Immunosuppressive protumoral M2 macrophages are important in pathogenesis, progression, and therapy resistance in glioblastoma (GBM) and provide a target for therapy. Recently oncolytic virotherapy in murine models was shown to change these M2 macrophages toward the pro-inflammatory and antitumoral M1 phenotype. Here we study the effects of the oncolytic virotherapy Delta24-RGD in humans, using both in vitro models and patient material. Methods. Human monocyte-derived macrophages were co-cultured with Delta24-RGD-infected primary glioma stem-like cells (GSCs) and were analyzed for their immunophenotype, cytokine expression, and secretion profiles. Cerebrospinal fluid (CSF) from 18 Delta24-RGD-treated patients was analyzed for inflammatory cytokine levels, and the effects of these CSF samples on macrophage phenotype in vitro were determined. In addition, tumor macrophages in resected material from a Delta24-RGD-treated GBM patient were compared with 5 control GBM patient samples by flow cytometry. Results. Human monocyte-derived M2 macrophages co-cultured with Delta24-RGD-infected GSCs shifted toward an M1-immunophenotype, coinciding with pro-inflammatory gene expression and cytokine production. This phenotypic switch was induced by the concerted effects of a change in tumor-produced soluble factors and the presence of viral particles. CSF samples from Delta24-RGD-treated GBM patients revealed cytokine levels indicative of a pro-inflammatory microenvironment. Furthermore, tumoral macrophages in a Delta24-RGD-treated patient showed significantly greater M1 characteristics than in control GBM tissue. Conclusion. Together these in vitro and patient studies demonstrate that local Delta24-RGD therapy may provide a therapeutic tool to promote a prolonged shift in the protumoral M2 macrophages toward M1 in human GBM, inducing a pro-inflammatory and potentially tumor-detrimental microenvironment.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85054779979&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/29796615

U2 - 10.1093/neuonc/noy082

DO - 10.1093/neuonc/noy082

M3 - Article

VL - 20

SP - 1494

EP - 1504

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - 11

ER -