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Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth
- Source :
- Clin Cancer Res
- Publication Year :
- 2019
- Publisher :
- American Association for Cancer Research (AACR), 2019.
-
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.
- Subjects :
- 0301 basic medicine
Cancer Research
Myeloid
medicine.medical_treatment
T cell
Article
B7-H1 Antigen
Mice
03 medical and health sciences
0302 clinical medicine
Immune system
PD-L1
Tumor Cells, Cultured
Tumor Microenvironment
medicine
Animals
Humans
Myeloid Cells
STAT3
Cell Proliferation
Immunosuppression Therapy
biology
Brain Neoplasms
Interleukin-6
business.industry
Immunotherapy
Prognosis
Mice, Inbred C57BL
Survival Rate
030104 developmental biology
medicine.anatomical_structure
Cytokine
Oncology
030220 oncology & carcinogenesis
STAT protein
biology.protein
Cancer research
Glioblastoma
business
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....9c095e88114efede78c6a926777d2cf6