Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment

Adela Wu, Russell Maxwell, Yuanxuan Xia, Pina Cardarelli, Miho Oyasu, Zineb Belcaid, Eileen Kim, Alice Hung, Andrew S. Luksik, Tomas Garzon-Muvdi, Christopher M. Jackson, Dimitrios Mathios, Debebe Theodros, John Cogswell, Henry Brem, Andrew Mark Pardoll, Michael Lim

Research output: Contribution to journalArticle

Abstract

Background: Emerging evidence suggests that myeloid cells play a critical role in glioblastoma (GBM) immunosuppression. Disappointing results of recent checkpoint inhibitor trials suggest that combination immunotherapy with alternative agents could be fruitful in overcoming immunosuppression. Overexpression of chemokine receptor CXCR4 is associated with poor prognosis in GBM. We investigate the treatment effects of combination immunotherapy with anti-PD-1 and anti-CXCR4 in a murine glioma model. Methods: C57BL/6 mice were implanted with GL261-Luc+ glioma cells and randomized into 4 arms: (1) control (2) anti-PD-1 (3) anti-CXCR4, and (4) anti-PD-1 and anti-CXCR4 therapy. Overall survival and median survival were assessed. Cell populations were assessed by flow cytometry. Results: Combination therapy conferred a significant survival benefit compared to control and monotherapy arms. Mice that received combination therapy demonstrated immune memory and decreased populations of immunosuppressive tumor-infiltrating leukocytes, such as monocytic myeloid-derived suppressor cells and microglia within the brain. Furthermore, combination therapy improved CD4+/CD8+ ratios in the brain as well as contributed to increased levels of pro-inflammatory cytokines. Conclusions: Anti-CXCR4 and anti-PD-1 combination immunotherapy modulates tumor-infiltrating populations of the glioma microenvironment. Targeting myeloid cells with anti-CXCR4 facilitates anti-PD-1 to promote an antitumor immune response and improved survival rates.

Original languageEnglish (US)
JournalJournal of neuro-oncology
DOIs
StatePublished - Jan 1 2019

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Tumor Microenvironment
Glioblastoma
Immunotherapy
Glioma
Myeloid Cells
Immunosuppression
Population
Therapeutics
CD4-CD8 Ratio
Chemokine Receptors
Brain
Microglia
Immunosuppressive Agents
Inbred C57BL Mouse
Neoplasms
Flow Cytometry
Leukocytes
Cytokines

Keywords

  • Checkpoint inhibitor
  • CXCR4
  • Glioma
  • Immunotherapy
  • PD-1

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment. / Wu, Adela; Maxwell, Russell; Xia, Yuanxuan; Cardarelli, Pina; Oyasu, Miho; Belcaid, Zineb; Kim, Eileen; Hung, Alice; Luksik, Andrew S.; Garzon-Muvdi, Tomas; Jackson, Christopher M.; Mathios, Dimitrios; Theodros, Debebe; Cogswell, John; Brem, Henry; Pardoll, Andrew Mark; Lim, Michael.

In: Journal of neuro-oncology, 01.01.2019.

Research output: Contribution to journalArticle

Wu, A, Maxwell, R, Xia, Y, Cardarelli, P, Oyasu, M, Belcaid, Z, Kim, E, Hung, A, Luksik, AS, Garzon-Muvdi, T, Jackson, CM, Mathios, D, Theodros, D, Cogswell, J, Brem, H, Pardoll, AM & Lim, M 2019, 'Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment', Journal of neuro-oncology. https://doi.org/10.1007/s11060-019-03172-5
Wu, Adela ; Maxwell, Russell ; Xia, Yuanxuan ; Cardarelli, Pina ; Oyasu, Miho ; Belcaid, Zineb ; Kim, Eileen ; Hung, Alice ; Luksik, Andrew S. ; Garzon-Muvdi, Tomas ; Jackson, Christopher M. ; Mathios, Dimitrios ; Theodros, Debebe ; Cogswell, John ; Brem, Henry ; Pardoll, Andrew Mark ; Lim, Michael. / Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment. In: Journal of neuro-oncology. 2019.
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T1 - Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment

AU - Wu, Adela

AU - Maxwell, Russell

AU - Xia, Yuanxuan

AU - Cardarelli, Pina

AU - Oyasu, Miho

AU - Belcaid, Zineb

AU - Kim, Eileen

AU - Hung, Alice

AU - Luksik, Andrew S.

AU - Garzon-Muvdi, Tomas

AU - Jackson, Christopher M.

AU - Mathios, Dimitrios

AU - Theodros, Debebe

AU - Cogswell, John

AU - Brem, Henry

AU - Pardoll, Andrew Mark

AU - Lim, Michael

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Emerging evidence suggests that myeloid cells play a critical role in glioblastoma (GBM) immunosuppression. Disappointing results of recent checkpoint inhibitor trials suggest that combination immunotherapy with alternative agents could be fruitful in overcoming immunosuppression. Overexpression of chemokine receptor CXCR4 is associated with poor prognosis in GBM. We investigate the treatment effects of combination immunotherapy with anti-PD-1 and anti-CXCR4 in a murine glioma model. Methods: C57BL/6 mice were implanted with GL261-Luc+ glioma cells and randomized into 4 arms: (1) control (2) anti-PD-1 (3) anti-CXCR4, and (4) anti-PD-1 and anti-CXCR4 therapy. Overall survival and median survival were assessed. Cell populations were assessed by flow cytometry. Results: Combination therapy conferred a significant survival benefit compared to control and monotherapy arms. Mice that received combination therapy demonstrated immune memory and decreased populations of immunosuppressive tumor-infiltrating leukocytes, such as monocytic myeloid-derived suppressor cells and microglia within the brain. Furthermore, combination therapy improved CD4+/CD8+ ratios in the brain as well as contributed to increased levels of pro-inflammatory cytokines. Conclusions: Anti-CXCR4 and anti-PD-1 combination immunotherapy modulates tumor-infiltrating populations of the glioma microenvironment. Targeting myeloid cells with anti-CXCR4 facilitates anti-PD-1 to promote an antitumor immune response and improved survival rates.

AB - Background: Emerging evidence suggests that myeloid cells play a critical role in glioblastoma (GBM) immunosuppression. Disappointing results of recent checkpoint inhibitor trials suggest that combination immunotherapy with alternative agents could be fruitful in overcoming immunosuppression. Overexpression of chemokine receptor CXCR4 is associated with poor prognosis in GBM. We investigate the treatment effects of combination immunotherapy with anti-PD-1 and anti-CXCR4 in a murine glioma model. Methods: C57BL/6 mice were implanted with GL261-Luc+ glioma cells and randomized into 4 arms: (1) control (2) anti-PD-1 (3) anti-CXCR4, and (4) anti-PD-1 and anti-CXCR4 therapy. Overall survival and median survival were assessed. Cell populations were assessed by flow cytometry. Results: Combination therapy conferred a significant survival benefit compared to control and monotherapy arms. Mice that received combination therapy demonstrated immune memory and decreased populations of immunosuppressive tumor-infiltrating leukocytes, such as monocytic myeloid-derived suppressor cells and microglia within the brain. Furthermore, combination therapy improved CD4+/CD8+ ratios in the brain as well as contributed to increased levels of pro-inflammatory cytokines. Conclusions: Anti-CXCR4 and anti-PD-1 combination immunotherapy modulates tumor-infiltrating populations of the glioma microenvironment. Targeting myeloid cells with anti-CXCR4 facilitates anti-PD-1 to promote an antitumor immune response and improved survival rates.

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KW - PD-1

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