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Title: The role of macrophages in the host response to radiation
Author: Jones, Keaton
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Emerging pre-clinical data suggests a role for radiation in eliciting antitumor immunity. Effective anti-tumour responses can be hindered by highly immunosuppressive tumour microenvironments. We aimed to investigate the role of macrophages in the immune response to radiation. We used the murine colorectal cancer cell line MC38 and the pancreatic cell line KPC for in vitro and in vivo work. To examine the immune response following irradiation, subcutaneous xenografts were analysed by flow cytometry. Further characterisation of macrophages was carried out by gene expression analyses of RNA from isolated cells, along with ex-vivo functional assays. To determine the effect of macrophage depletion, we used an antibody targeting macrophage colony stimulating factor (CSF-1). Single dose 10Gy irradiation to murine tumors, generated from colorectal (MC38) and pancreatic (KPC) cell lines induced Colony Stimulating Factor 1 (CSF-1). Coincident with the elevation in CSF1, CD11b+ F480+ macrophages increased in the tumors, peaking five days following irradiation. These tumor-associated macrophages (TAMs) from irradiated tumors were skewed toward an immunosuppressive phenotpye (CD206hi iNOSlo) and were more effective in suppressing CD8 T cell expansion ex vivo. Macrophage depletion via anti-CSF (aCSF) reduced macrophage numbers yet only achieved tumor growth delay when combined with radiation. The tumor growth delay from aCSF after radiation was abrogated by depletion of CD8 T cells. There was enhanced recognition of tumor cell antigens by T cells isolated from irradiated tumors, consistent with increased antigen priming. Radiation stimulated increased expression of PD-L1 on tumor cells, limiting antitumor responses. The addition of anti-PD-L1 resulted in improved tumor suppression and even regression in the highly resistant murine pancreatic cancer model. In summary we show that adaptive immunity induced by radiation is limited by the recruitment of highly M2 polarised immunosuppressive macrophages. Macrophage depletion with aCSF partly reduced the immunosuppression after radiation, but additional treatment with anti-PD-L1 was required to achieve tumor regression.
Supervisor: Muschel, Ruth Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available