Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth

Authors

• Jonathan B. Lamano, Department of Neurological Surgery, Northwestern University, Chicago, Illinois.
• Jason Balquidera Lamano, Department of Neurological Surgery, Northwestern University, Chicago, Illinois.
• Yuping D. Li, Department of Neurological Surgery, Northwestern University, Chicago, Illinois.
• Joseph D. DiDomenico, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona.Follow
• Winward Choy, Department of Neurological Surgery, University of California San Francisco, San Francisco, California.
• Dorina Veliceasa, Department of Neurological Surgery, Northwestern University, Chicago, Illinois.
• Daniel E. Oyon, Department of Neurological Surgery, Northwestern University, Chicago, Illinois.
• Shayan Fakurnejad, Stanford School of Medicine, Stanford University, Stanford, California.
• Leonel Ampie, Department of Neurosurgery, University of Virginia School of Medicine, University of Virginia, Charlottesville, Virginia.
• Kartik Kesavabhotla, Department of Neurological Surgery, Northwestern University, Chicago, Illinois.
• Rajwant Kaur, Department of Neurological Surgery, Northwestern University, Chicago, Illinois.
• Gurvinder Kaur, Department of Neurological Surgery, Northwestern University, Chicago, Illinois.
• Dauren Biyashev, Department of Neurological Surgery, Northwestern University, Chicago, Illinois.
• Dusten J. Unruh, Department of Neurological Surgery, Northwestern University, Chicago, Illinois.
• Craig M. Horbinski, Department of Neurological Surgery, Northwestern University, Chicago, Illinois.
• C David James, Department of Neurological Surgery, Northwestern University, Chicago, Illinois.
• Andrew T. Parsa
• Orin Bloch, Department of Neurological Surgery, Northwestern University, Chicago, Illinois. orin.bloch@northwestern.edu.

Document Type

Article

Abstract

PURPOSE: Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. Although GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation. EXPERIMENTAL DESIGN: Conditioned media from patient-derived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate naïve myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors. RESULTS: GBM-derived IL6 was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a STAT3-dependent mechanism. Inhibition of IL6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL6 therapy proved to be CD8 T-cell dependent, and the antitumor activity was additive with that provided by programmed death-1 (PD-1)-targeted immunotherapy. CONCLUSIONS: Our findings suggest that disruption of IL6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated antitumor responses against GBM.

Medical Subject Headings

Animals; B7-H1 Antigen (immunology); Brain Neoplasms (immunology, metabolism, pathology); Cell Proliferation; Glioblastoma (immunology, metabolism, pathology); Humans; Immunosuppression Therapy; Interleukin-6 (blood, immunology, pharmacology); Mice; Mice, Inbred C57BL; Myeloid Cells (immunology); Prognosis; Survival Rate; Tumor Cells, Cultured; Tumor Microenvironment (immunology)

Publication Date

6-15-2019

Publication Title

Clinical cancer research : an official journal of the American Association for Cancer Research

E-ISSN

1557-3265

Volume

25

Issue

12

First Page

3643

Last Page

3657

PubMed ID

30824583

Digital Object Identifier (DOI)

10.1158/1078-0432.CCR-18-2402

Recommended Citation

Lamano, Jonathan B.; Lamano, Jason Balquidera; Li, Yuping D.; DiDomenico, Joseph D.; Choy, Winward; Veliceasa, Dorina; Oyon, Daniel E.; Fakurnejad, Shayan; Ampie, Leonel; Kesavabhotla, Kartik; Kaur, Rajwant; Kaur, Gurvinder; Biyashev, Dauren; Unruh, Dusten J.; Horbinski, Craig M.; James, C David; Parsa, Andrew T.; and Bloch, Orin, "Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth" (2019). Neurosurgery. 2173.
https://scholar.barrowneuro.org/neurosurgery/2173