Anti–PD-L1 antibody direct activation of macrophages contributes to a radiation-induced abscopal response in glioblastoma. Issue 5 (3rd December 2019)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Neuro-oncology. Volume 22:Issue 5(2020)
• Page Start: 639
• Page End: 651
• Publication Date: 2019-12-03
• Subjects: abscopal effect -- glioblastoma -- macrophages -- radiation -- T cells; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz226
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Background: Most glioblastomas recur near prior radiation treatment sites. Future clinical success will require achieving and optimizing an "abscopal effect, " whereby unirradiated neoplastic cells outside treatment sites are recognized and attacked by the immune system. Radiation combined with anti–programmed cell death ligand 1 (PD-L1) demonstrated modest efficacy in phase II human glioblastoma clinical trials, but the mechanism and relevance of the abscopal effect during this response remain unknown. Methods: We modified an immune-competent, genetically driven mouse glioma model (forced platelet derived growth factor [PDGF] expression + phosphatase and tensin homolog loss) where a portion of the tumor burden is irradiated (PDGF) and another unirradiated 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 epidermal growth factor receptor variant III (EGFRvIII) (PDGF + EGFRvIII). Statistical tests were two-sided. Results: Following radiation of one lesion, anti–PD-L1 immunotherapy enhanced the abscopal response to the unirradiated lesion. In PDGF-driven gliomas without tumor neoepitope (PDGF + luciferase, n = 8), the abscopal response occurred via anti–PD-L1 driven, extracellular signal-regulated kinase–mediated, bone marrow–derived macrophage phagocytosis of adjacent unirradiated tumor cells, with modest survival implications (median survival 41 days vs radiation alone 37.5 days, P = 0.03). 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 = 0.001). 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.