Irradiation-Modulated Murine Brain Microenvironment Enhances GL261-Tumor Growth and Inhibits Anti-PD-L1 Immunotherapy
PurposeClinical evidence suggests radiation induces changes in the brain microenvironment that affect subsequent response to treatment. This study investigates the effect of previous radiation, delivered six weeks prior to orthotopic tumor implantation, on subsequent tumor growth and therapeutic res...
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Frontiers Media S.A.
2021-06-01
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Series: | Frontiers in Oncology |
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Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.693146/full |
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language |
English |
format |
Article |
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DOAJ |
author |
Joel R. Garbow Joel R. Garbow Tanner M. Johanns Tanner M. Johanns Xia Ge John A. Engelbach Liya Yuan Sonika Dahiya Christina I. Tsien Feng Gao Keith M. Rich Joseph J. H. Ackerman Joseph J. H. Ackerman Joseph J. H. Ackerman Joseph J. H. Ackerman |
spellingShingle |
Joel R. Garbow Joel R. Garbow Tanner M. Johanns Tanner M. Johanns Xia Ge John A. Engelbach Liya Yuan Sonika Dahiya Christina I. Tsien Feng Gao Keith M. Rich Joseph J. H. Ackerman Joseph J. H. Ackerman Joseph J. H. Ackerman Joseph J. H. Ackerman Irradiation-Modulated Murine Brain Microenvironment Enhances GL261-Tumor Growth and Inhibits Anti-PD-L1 Immunotherapy Frontiers in Oncology MRI radiation tumor microenvironment immunotherapy checkpoint inhibitors |
author_facet |
Joel R. Garbow Joel R. Garbow Tanner M. Johanns Tanner M. Johanns Xia Ge John A. Engelbach Liya Yuan Sonika Dahiya Christina I. Tsien Feng Gao Keith M. Rich Joseph J. H. Ackerman Joseph J. H. Ackerman Joseph J. H. Ackerman Joseph J. H. Ackerman |
author_sort |
Joel R. Garbow |
title |
Irradiation-Modulated Murine Brain Microenvironment Enhances GL261-Tumor Growth and Inhibits Anti-PD-L1 Immunotherapy |
title_short |
Irradiation-Modulated Murine Brain Microenvironment Enhances GL261-Tumor Growth and Inhibits Anti-PD-L1 Immunotherapy |
title_full |
Irradiation-Modulated Murine Brain Microenvironment Enhances GL261-Tumor Growth and Inhibits Anti-PD-L1 Immunotherapy |
title_fullStr |
Irradiation-Modulated Murine Brain Microenvironment Enhances GL261-Tumor Growth and Inhibits Anti-PD-L1 Immunotherapy |
title_full_unstemmed |
Irradiation-Modulated Murine Brain Microenvironment Enhances GL261-Tumor Growth and Inhibits Anti-PD-L1 Immunotherapy |
title_sort |
irradiation-modulated murine brain microenvironment enhances gl261-tumor growth and inhibits anti-pd-l1 immunotherapy |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2021-06-01 |
description |
PurposeClinical evidence suggests radiation induces changes in the brain microenvironment that affect subsequent response to treatment. This study investigates the effect of previous radiation, delivered six weeks prior to orthotopic tumor implantation, on subsequent tumor growth and therapeutic response to anti-PD-L1 therapy in an intracranial mouse model, termed the Radiation Induced Immunosuppressive Microenvironment (RI2M) model.Method and MaterialsC57Bl/6 mice received focal (hemispheric) single-fraction, 30-Gy radiation using the Leksell GammaKnife® Perfexion™, a dose that does not produce frank/gross radiation necrosis. Non-irradiated GL261 glioblastoma tumor cells were implanted six weeks later into the irradiated hemisphere. Lesion volume was measured longitudinally by in vivo MRI. In a separate experiment, tumors were implanted into either previously irradiated (30 Gy) or non-irradiated mouse brain, mice were treated with anti-PD-L1 antibody, and Kaplan-Meier survival curves were constructed. Mouse brains were assessed by conventional hematoxylin and eosin (H&E) staining, IBA-1 staining, which detects activated microglia and macrophages, and fluorescence-activated cell sorting (FACS) analysis.ResultsTumors in previously irradiated brain display aggressive, invasive growth, characterized by viable tumor and large regions of hemorrhage and necrosis. Mice challenged intracranially with GL261 six weeks after prior intracranial irradiation are unresponsive to anti-PD-L1 therapy. K-M curves demonstrate a statistically significant difference in survival for tumor-bearing mice treated with anti-PD-L1 antibody between RI2M vs. non-irradiated mice. The most prominent immunologic change in the post-irradiated brain parenchyma is an increased frequency of activated microglia.ConclusionsThe RI2M model focuses on the persisting (weeks-to-months) impact of radiation applied to normal, control-state brain on the growth characteristics and immunotherapy response of subsequently implanted tumor. GL261 tumors growing in the RI2M grew markedly more aggressively, with tumor cells admixed with regions of hemorrhage and necrosis, and showed a dramatic loss of response to anti-PD-L1 therapy compared to tumors in non-irradiated brain. IHC and FACS analyses demonstrate increased frequency of activated microglia, which correlates with loss of sensitivity to checkpoint immunotherapy. Given that standard-of-care for primary brain tumor following resection includes concurrent radiation and chemotherapy, these striking observations strongly motivate detailed assessment of the late effects of the RI2M on tumor growth and therapeutic efficacy. |
topic |
MRI radiation tumor microenvironment immunotherapy checkpoint inhibitors |
url |
https://www.frontiersin.org/articles/10.3389/fonc.2021.693146/full |
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doaj-df0d9d4ab43a4809bf80c2fe665a833b2021-06-24T04:43:59ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-06-011110.3389/fonc.2021.693146693146Irradiation-Modulated Murine Brain Microenvironment Enhances GL261-Tumor Growth and Inhibits Anti-PD-L1 ImmunotherapyJoel R. Garbow0Joel R. Garbow1Tanner M. Johanns2Tanner M. Johanns3Xia Ge4John A. Engelbach5Liya Yuan6Sonika Dahiya7Christina I. Tsien8Feng Gao9Keith M. Rich10Joseph J. H. Ackerman11Joseph J. H. Ackerman12Joseph J. H. Ackerman13Joseph J. H. Ackerman14Department of Radiology, Washington University, Saint Louis, MO, United StatesAlvin J. Siteman Cancer Center, Washington University, Saint Louis, MO, United StatesDepartment of Internal Medicine, Washington University, Saint Louis, MO, United StatesAlvin J. Siteman Cancer Center, Washington University, Saint Louis, MO, United StatesDepartment of Radiology, Washington University, Saint Louis, MO, United StatesDepartment of Radiology, Washington University, Saint Louis, MO, United StatesDepartment of Neurosurgery, Washington University, Saint Louis, MO, United StatesDivision of Neuropathology, Department of Pathology and Immunology, Washington University, Saint Louis, MO, United StatesDepartment of Radiation Oncology, Washington University, Saint Louis, MO, United StatesDepartment of Surgery, Washington University, Saint Louis, MO, United StatesDepartment of Neurosurgery, Washington University, Saint Louis, MO, United StatesDepartment of Radiology, Washington University, Saint Louis, MO, United StatesAlvin J. Siteman Cancer Center, Washington University, Saint Louis, MO, United StatesDepartment of Internal Medicine, Washington University, Saint Louis, MO, United StatesDepartment of Chemistry, Washington University, Saint Louis, MO, United StatesPurposeClinical evidence suggests radiation induces changes in the brain microenvironment that affect subsequent response to treatment. This study investigates the effect of previous radiation, delivered six weeks prior to orthotopic tumor implantation, on subsequent tumor growth and therapeutic response to anti-PD-L1 therapy in an intracranial mouse model, termed the Radiation Induced Immunosuppressive Microenvironment (RI2M) model.Method and MaterialsC57Bl/6 mice received focal (hemispheric) single-fraction, 30-Gy radiation using the Leksell GammaKnife® Perfexion™, a dose that does not produce frank/gross radiation necrosis. Non-irradiated GL261 glioblastoma tumor cells were implanted six weeks later into the irradiated hemisphere. Lesion volume was measured longitudinally by in vivo MRI. In a separate experiment, tumors were implanted into either previously irradiated (30 Gy) or non-irradiated mouse brain, mice were treated with anti-PD-L1 antibody, and Kaplan-Meier survival curves were constructed. Mouse brains were assessed by conventional hematoxylin and eosin (H&E) staining, IBA-1 staining, which detects activated microglia and macrophages, and fluorescence-activated cell sorting (FACS) analysis.ResultsTumors in previously irradiated brain display aggressive, invasive growth, characterized by viable tumor and large regions of hemorrhage and necrosis. Mice challenged intracranially with GL261 six weeks after prior intracranial irradiation are unresponsive to anti-PD-L1 therapy. K-M curves demonstrate a statistically significant difference in survival for tumor-bearing mice treated with anti-PD-L1 antibody between RI2M vs. non-irradiated mice. The most prominent immunologic change in the post-irradiated brain parenchyma is an increased frequency of activated microglia.ConclusionsThe RI2M model focuses on the persisting (weeks-to-months) impact of radiation applied to normal, control-state brain on the growth characteristics and immunotherapy response of subsequently implanted tumor. GL261 tumors growing in the RI2M grew markedly more aggressively, with tumor cells admixed with regions of hemorrhage and necrosis, and showed a dramatic loss of response to anti-PD-L1 therapy compared to tumors in non-irradiated brain. IHC and FACS analyses demonstrate increased frequency of activated microglia, which correlates with loss of sensitivity to checkpoint immunotherapy. Given that standard-of-care for primary brain tumor following resection includes concurrent radiation and chemotherapy, these striking observations strongly motivate detailed assessment of the late effects of the RI2M on tumor growth and therapeutic efficacy.https://www.frontiersin.org/articles/10.3389/fonc.2021.693146/fullMRIradiationtumormicroenvironmentimmunotherapycheckpoint inhibitors |