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

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.

• Authors: 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, Drew M Pardoll, Michael Lim
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 143 Issue 2 Pg. 241-249 (Jun 2019) ISSN: 1573-7373 [Electronic] United States
• PMID: 31025274 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Immunological
• CXCR4 protein, mouse
• Cytokines
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Receptors, CXCR4

Topics

• Animals
• Antineoplastic Agents, Immunological (pharmacology)
• Brain Neoplasms (drug therapy, immunology, mortality, pathology)
• Cytokines (metabolism)
• Female
• Glioblastoma (drug therapy, immunology, mortality, pathology)
• Humans
• Immunotherapy
• Mice
• Mice, Inbred C57BL
• Myeloid Cells (drug effects, immunology)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, immunology)
• Receptors, CXCR4 (antagonists & inhibitors, immunology)
• Survival Rate
• Tumor Microenvironment (drug effects, immunology)
• Xenograft Model Antitumor Assays