Abstract
Purpose: Upregulation of programmed death-ligand 1 (PDL1) 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 patientderived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate näve 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3643-3657 |
| Number of pages | 15 |
| Journal | Clinical Cancer Research |
| Volume | 25 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jun 15 2019 |
Funding
The authors would like to thank the following core facilities at Northwestern University, without which the current study would not be possible: the Nervous System Tumor Bank (supported by P50CA221747 SPORE for Translational Approaches to Brain Cancer), the Interdepartmental ImmunoBiology Flow Cytometry Core Facility, the DNA/RNA Delivery Core of the Skin Disease Research Center for providing us the service of knocking down murine IL6 protein in GL261 cell lines by CRISPR-Cas9 gene editing, Center for Advanced Microscopy/Nikon Imaging Center (supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center), the Mouse Histology and Phenotyping Laboratory, the Center for Comparative Medicine, and the Quantitative Data Sciences Core (supported by NCI CCSG P30 CA060553). The authors would also like to thank Dr. Stephen D. Miller for his guidance in study design and interpretation of results and Lisa P. Magnusson for her assistance in animal studies. This work was supported by the NIH/ National Cancer Institute (NCI) Ruth L. Kirschtein National Research Service Award F30 (CA206413; to Jonathan B. Lamano), NIH/NCI R01 (CA164714; to O. Bloch), and NIH/National Institute of Neurological Disorders and Stroke (NINDS) R00 (NS078055; to O. Bloch). J.D. DiDomenico was supported by the Alpha Omega Alpha Honor Medical Society (AOA) Carolyn L. Kuckein Student Research Fellowship and the American Medical Association Seed Fellowship. Y.D. Li and L. Ampie were supported by individual student fellowships from the Howard Hughes Medical Institute. G. Kaur was supported by NIH/NINDS F32 (NS101884).
ASJC Scopus subject areas
- General Medicine
