Glioblastoma-derived IL6 induces immunosuppressive peripheral myeloid cell PD-L1 and promotes tumor growth

Jonathan B. Lamano, Jason Balquidera Lamano, Yuping D. Li, Joseph D. DiDomenico, Winward Choy, Dorina Veliceasa, Daniel E. Oyon, Shayan Fakurnejad, Leonel Ampie, Kartik Kesavabhotla, Rajwant Kaur, Gurvinder Kaur, Dauren Biyashev, Dusten J. Unruh, Craig M. Horbinski, C. David James, Andrew T. Parsa, Orin Bloch

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)3643-3657
Number of pages15
JournalClinical Cancer Research
Volume25
Issue number12
DOIs
StatePublished - Jun 15 2019
Externally publishedYes

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Myeloid Cells
Glioblastoma
Immunosuppressive Agents
Interleukin-6
Immunosuppression
Cytokines
Growth
Immunotherapy
Neoplasms
Up-Regulation
Conditioned Culture Medium
Inbred C57BL Mouse
Glioma
Flow Cytometry
Research Design
Vaccines
Cell Culture Techniques
Ligands
T-Lymphocytes
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Glioblastoma-derived IL6 induces immunosuppressive peripheral myeloid cell PD-L1 and promotes tumor growth. / 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.

In: Clinical Cancer Research, Vol. 25, No. 12, 15.06.2019, p. 3643-3657.

Research output: Contribution to journalArticle

Lamano, JB, Lamano, JB, Li, YD, DiDomenico, JD, Choy, W, Veliceasa, D, Oyon, DE, Fakurnejad, S, Ampie, L, Kesavabhotla, K, Kaur, R, Kaur, G, Biyashev, D, Unruh, DJ, Horbinski, CM, James, CD, Parsa, AT & Bloch, O 2019, 'Glioblastoma-derived IL6 induces immunosuppressive peripheral myeloid cell PD-L1 and promotes tumor growth', Clinical Cancer Research, vol. 25, no. 12, pp. 3643-3657. https://doi.org/10.1158/1078-0432.CCR-18-2402
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. / Glioblastoma-derived IL6 induces immunosuppressive peripheral myeloid cell PD-L1 and promotes tumor growth. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 12. pp. 3643-3657.
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title = "Glioblastoma-derived IL6 induces immunosuppressive peripheral myeloid cell PD-L1 and promotes tumor growth",
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 n{\"a}ve 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.",
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T1 - Glioblastoma-derived IL6 induces immunosuppressive peripheral myeloid cell PD-L1 and promotes tumor growth

AU - Lamano, Jonathan B.

AU - Lamano, Jason Balquidera

AU - Li, Yuping D.

AU - DiDomenico, Joseph D.

AU - Choy, Winward

AU - Veliceasa, Dorina

AU - Oyon, Daniel E.

AU - Fakurnejad, Shayan

AU - Ampie, Leonel

AU - Kesavabhotla, Kartik

AU - Kaur, Rajwant

AU - Kaur, Gurvinder

AU - Biyashev, Dauren

AU - Unruh, Dusten J.

AU - Horbinski, Craig M.

AU - James, C. David

AU - Parsa, Andrew T.

AU - Bloch, Orin

PY - 2019/6/15

Y1 - 2019/6/15

N2 - 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.

AB - 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.

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