Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade
Abstract Emerging evidence suggests a role for radiation in eliciting anti‐tumour immunity. We aimed to investigate the role of macrophages in modulating the immune response to radiation. Irradiation to murine tumours generated from colorectal (MC38) and pancreatic (KPC) cell lines induced colony‐st...
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201809342 |
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| author | Keaton I Jones Jiske Tiersma Arseniy E Yuzhalin Alex N Gordon‐Weeks Jon Buzzelli Jae Hong Im Ruth J Muschel |
| author_facet | Keaton I Jones Jiske Tiersma Arseniy E Yuzhalin Alex N Gordon‐Weeks Jon Buzzelli Jae Hong Im Ruth J Muschel |
| author_sort | Keaton I Jones |
| collection | DOAJ |
| description | Abstract Emerging evidence suggests a role for radiation in eliciting anti‐tumour immunity. We aimed to investigate the role of macrophages in modulating the immune response to radiation. Irradiation to murine tumours generated from colorectal (MC38) and pancreatic (KPC) cell lines induced colony‐stimulating factor 1 (CSF‐1). Coincident with the elevation in CSF‐1, macrophages increased in tumours, peaking 5 days following irradiation. These tumour‐associated macrophages (TAMs) were skewed towards an immunosuppressive phenotype. Macrophage depletion via anti‐CSF (aCSF) reduced macrophage numbers, yet only achieved tumour growth delay when combined with radiation. The tumour growth delay from aCSF after radiation was abrogated by depletion of CD8 T cells. There was enhanced recognition of tumour cell antigens by T cells isolated from irradiated tumours, consistent with increased antigen priming. The addition of anti‐PD‐L1 (aPD‐L1) resulted in improved tumour suppression and even regression in some tumours. In summary, we show that adaptive immunity induced by radiation is limited by the recruitment of highly immunosuppressive macrophages. Macrophage depletion partly reduced immunosuppression, but additional treatment with anti‐PD‐L1 was required to achieve tumour regression. |
| format | Article |
| id | doaj-art-be307394213f42598b2d3a0581459ea3 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2018-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-be307394213f42598b2d3a0581459ea32025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-11-01101211610.15252/emmm.201809342Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockadeKeaton I Jones0Jiske Tiersma1Arseniy E Yuzhalin2Alex N Gordon‐Weeks3Jon Buzzelli4Jae Hong Im5Ruth J Muschel6Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Churchill Hospital, University of OxfordDepartment of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Churchill Hospital, University of OxfordDepartment of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Churchill Hospital, University of OxfordNuffield Department of Surgical Sciences, John Radcliffe Hospital, University of OxfordDepartment of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Churchill Hospital, University of OxfordDepartment of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Churchill Hospital, University of OxfordDepartment of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, Churchill Hospital, University of OxfordAbstract Emerging evidence suggests a role for radiation in eliciting anti‐tumour immunity. We aimed to investigate the role of macrophages in modulating the immune response to radiation. Irradiation to murine tumours generated from colorectal (MC38) and pancreatic (KPC) cell lines induced colony‐stimulating factor 1 (CSF‐1). Coincident with the elevation in CSF‐1, macrophages increased in tumours, peaking 5 days following irradiation. These tumour‐associated macrophages (TAMs) were skewed towards an immunosuppressive phenotype. Macrophage depletion via anti‐CSF (aCSF) reduced macrophage numbers, yet only achieved tumour growth delay when combined with radiation. The tumour growth delay from aCSF after radiation was abrogated by depletion of CD8 T cells. There was enhanced recognition of tumour cell antigens by T cells isolated from irradiated tumours, consistent with increased antigen priming. The addition of anti‐PD‐L1 (aPD‐L1) resulted in improved tumour suppression and even regression in some tumours. In summary, we show that adaptive immunity induced by radiation is limited by the recruitment of highly immunosuppressive macrophages. Macrophage depletion partly reduced immunosuppression, but additional treatment with anti‐PD‐L1 was required to achieve tumour regression.https://doi.org/10.15252/emmm.201809342immunosuppressionimmunotherapymacrophageradiation |
| spellingShingle | Keaton I Jones Jiske Tiersma Arseniy E Yuzhalin Alex N Gordon‐Weeks Jon Buzzelli Jae Hong Im Ruth J Muschel Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade EMBO Molecular Medicine immunosuppression immunotherapy macrophage radiation |
| title | Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade |
| title_full | Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade |
| title_fullStr | Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade |
| title_full_unstemmed | Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade |
| title_short | Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade |
| title_sort | radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade |
| topic | immunosuppression immunotherapy macrophage radiation |
| url | https://doi.org/10.15252/emmm.201809342 |
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