Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth
©2019 American Association for Cancer Research..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 25(2019), 12 vom: 15. Juni, Seite 3643-3657 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lamano, Jonathan B [VerfasserIn] |
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| Links: |
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| Themen: |
B7-H1 Antigen |
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| Anmerkungen: |
Date Completed 19.08.2020 Date Revised 12.10.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-18-2402 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM294488952 |
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| 100 | 1 | |a Lamano, Jonathan B |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 19.08.2020 | ||
| 500 | |a Date Revised 12.10.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2019 American Association for Cancer Research. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a B7-H1 Antigen |2 NLM | |
| 650 | 7 | |a CD274 protein, human |2 NLM | |
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| 700 | 1 | |a Lamano, Jason Balquidera |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yuping D |e verfasserin |4 aut | |
| 700 | 1 | |a DiDomenico, Joseph D |e verfasserin |4 aut | |
| 700 | 1 | |a Choy, Winward |e verfasserin |4 aut | |
| 700 | 1 | |a Veliceasa, Dorina |e verfasserin |4 aut | |
| 700 | 1 | |a Oyon, Daniel E |e verfasserin |4 aut | |
| 700 | 1 | |a Fakurnejad, Shayan |e verfasserin |4 aut | |
| 700 | 1 | |a Ampie, Leonel |e verfasserin |4 aut | |
| 700 | 1 | |a Kesavabhotla, Kartik |e verfasserin |4 aut | |
| 700 | 1 | |a Kaur, Rajwant |e verfasserin |4 aut | |
| 700 | 1 | |a Kaur, Gurvinder |e verfasserin |4 aut | |
| 700 | 1 | |a Biyashev, Dauren |e verfasserin |4 aut | |
| 700 | 1 | |a Unruh, Dusten J |e verfasserin |4 aut | |
| 700 | 1 | |a Horbinski, Craig M |e verfasserin |4 aut | |
| 700 | 1 | |a James, C David |e verfasserin |4 aut | |
| 700 | 1 | |a Parsa, Andrew T |e verfasserin |4 aut | |
| 700 | 1 | |a Bloch, Orin |e verfasserin |4 aut | |
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