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Anti-PD-L1 antibody direct activation of macrophages contributes to a radiation-induced abscopal response in glioblastoma


Ene, Chibawanye I; Kreuser, Shannon A; Jung, Miyeon; Zhang, Huajia; Arora, Sonali; White Moyes, Kara; Szulzewsky, Frank; Barber, Jason; Cimino, Patrick J; Wirsching, Hans-Georg; Patel, Anoop; Kong, Paul; Woodiwiss, Timothy R; Durfy, Sharon J; Houghton, A McGarry; Pierce, Robert H; Parney, Ian F; Crane, Courtney A; Holland, Eric C (2020). Anti-PD-L1 antibody direct activation of macrophages contributes to a radiation-induced abscopal response in glioblastoma. Neuro-Oncology, 22(5):639-651.

Abstract

BACKGROUND
Most glioblastoma recurrences occur near prior radiation treatment sites. Future clinical success will require achieving and optimizing an 'abscopal effect', whereby un-irradiated neoplastic cells outside treatment sites are recognized and attacked by the immune system. Radiation combined with anti-PD-L1 demonstrated modest efficacy in phase II human glioblastoma clinical trials, but the mechanism and relevance of the abscopal effect during this response remains unknown.
METHODS
We modified an immune-competent, genetically-driven mouse glioma model (forced PDGF expression + PTEN loss) where a portion of the tumor burden is irradiated (PDGF) and another un-irradiated luciferase expressing tumor (PDGF+Luciferase) is used as a readout of the abscopal effect following systemic anti-PD-L1 immunotherapy. We assessed relevance of tumor neoepitope during the abscopal response by inducing expression of EGFRvIII (PDGF+EGFRvIII). Statistical tests were two-sided.
RESULTS
Following radiation of one lesion, anti-PD-L1 immunotherapy enhanced the abscopal response to the un-irradiated lesion. In PDGF-driven gliomas without tumor neoepitope (PDGF+Luciferase, n=8), the abscopal response occurred via anti-PD-L1-driven, ERK-mediated, bone marrow-derived macrophage phagocytosis of adjacent un-irradiated tumor cells, with modest survival implications (median survival 41 days vs. radiation alone 37.5 days, P=.03). In PDGF-driven gliomas with tumor neoepitope (PDGF+EGFRvIII, n=8), anti-PD-L1-enhanced abscopal response was associated with macrophage and T-cell infiltration and increased survival benefit (median survival 36 days vs. radiation alone 28 days, P=.001).
CONCLUSION
Our results indicate that anti-PD-L1 immunotherapy enhances a radiation induced abscopal response via canonical T-cell activation and direct macrophage activation in glioblastoma.

Abstract

BACKGROUND
Most glioblastoma recurrences occur near prior radiation treatment sites. Future clinical success will require achieving and optimizing an 'abscopal effect', whereby un-irradiated neoplastic cells outside treatment sites are recognized and attacked by the immune system. Radiation combined with anti-PD-L1 demonstrated modest efficacy in phase II human glioblastoma clinical trials, but the mechanism and relevance of the abscopal effect during this response remains unknown.
METHODS
We modified an immune-competent, genetically-driven mouse glioma model (forced PDGF expression + PTEN loss) where a portion of the tumor burden is irradiated (PDGF) and another un-irradiated luciferase expressing tumor (PDGF+Luciferase) is used as a readout of the abscopal effect following systemic anti-PD-L1 immunotherapy. We assessed relevance of tumor neoepitope during the abscopal response by inducing expression of EGFRvIII (PDGF+EGFRvIII). Statistical tests were two-sided.
RESULTS
Following radiation of one lesion, anti-PD-L1 immunotherapy enhanced the abscopal response to the un-irradiated lesion. In PDGF-driven gliomas without tumor neoepitope (PDGF+Luciferase, n=8), the abscopal response occurred via anti-PD-L1-driven, ERK-mediated, bone marrow-derived macrophage phagocytosis of adjacent un-irradiated tumor cells, with modest survival implications (median survival 41 days vs. radiation alone 37.5 days, P=.03). In PDGF-driven gliomas with tumor neoepitope (PDGF+EGFRvIII, n=8), anti-PD-L1-enhanced abscopal response was associated with macrophage and T-cell infiltration and increased survival benefit (median survival 36 days vs. radiation alone 28 days, P=.001).
CONCLUSION
Our results indicate that anti-PD-L1 immunotherapy enhances a radiation induced abscopal response via canonical T-cell activation and direct macrophage activation in glioblastoma.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:15 May 2020
Deposited On:08 Jan 2020 10:15
Last Modified:01 Jan 2021 19:04
Publisher:Oxford University Press
ISSN:1522-8517
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/neuonc/noz226
PubMed ID:31793634

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