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