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

• Published in: Clinical cancer research Vol. 25; no. 12; pp. 3643 - 3657
• Main Authors: 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., Bloch, Orin
• Format: Journal Article
• Language: English
• Published: United States 15.06.2019
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-2402

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. 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 utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors. 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. 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.