Radiation response and combination target discovery in a novel model of rectal cancer
<p>Rectal cancer is typically treated with radiotherapy, with or without chemotherapy, prior to surgical resection of the tumour. However, in patients that respond poorly to radiation, tumours largely lack significant immune cells within the surrounding milieu and present with a CAF-rich strom...
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| Format: | Disertacija |
| Jezik: | English |
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2024
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| _version_ | 1826313508794400768 |
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| author | Beach, CJ |
| author2 | Leedham, S |
| author_facet | Leedham, S Beach, CJ |
| author_sort | Beach, CJ |
| collection | OXFORD |
| description | <p>Rectal cancer is typically treated with radiotherapy, with or without chemotherapy, prior to surgical resection of the tumour. However, in patients that respond poorly to radiation, tumours largely lack significant immune cells within the surrounding milieu and present with a CAF-rich stroma. We have recapitulated this radioresistant phenotype in vivo through the implantation of Apcfl/fl, KrasG12D/+, Trp53fl/fl, TgfbrIfl/fl (AKPT) organoids. Here, through the irradiation of the heterotopic AKPT model, we have identified two targets for inhibition to augment the anti-tumour effect of radiation: complement C5a receptor 1 (C5aR1) and transforming growth factor beta (TGF-β).</p>
<p>We demonstrated that inhibiting C5aR1 increased the effectiveness of irradiation in the AKPT model both in vitro and in vivo. Inhibiting C5aR1 in vitro had a direct impact on tumour cell radiosensitivity in the AKPT organoid model. In vivo we demonstrated that bolstering radiation through C5aR1 inhibition acts independently to the T-cell population, as shown in athymic mice bearing AKPT tumours heterotopically. Furthermore, we hypothesise that additional effects on the macrophage and cancer-associated fibroblast (CAF) populations could contribute to the augmentation of radiation anti-tumour effects when C5aR1 is inhibited. We demonstrate an increase in the inflammatory macrophage population, as well as a shift in the CAF phenotype. Interestingly, the modest radiosensitisation observed in vitro suggest that¸ in the in vivo AKPT model, mechanisms altering the macrophage and CAF populations may be of greater importance than increased intrinsic radiosensitivity.</p>
<p>We also demonstrate that the inhibition of TGF-β increased the effectiveness of radiation in vivo in the AKPT heterotopic model. Furthermore, we show that the inhibition of this multifunctional cytokine, when combined with irradiation, has a dramatic effect on both the immune cells and CAFs within the tumour milieu. These changes include a significant increase of cytotoxic T-cell infiltration of the tumour epithelium, a significant decrease in the Treg population, a shift in the macrophages toward a more inflammatory phenotype, and a shift in the CAF phenotype. These changes were reflected by the enrichment of immunogenic gene signatures in the AKPT model after treatment with radiation combined with TGF-β inhibition, with immunosuppressive signatures showing a corresponding negative enrichment. We hypothesise that the shift in the CAF population phenotype is directly linked to the increase immunogenic action against the tumour. We further suggest that in the AKPT rectal cancer model, the CAF population acts to orchestrate the sustained immune response after irradiation, provided TGF-β is inhibited.</p> |
| first_indexed | 2024-09-25T04:16:20Z |
| format | Thesis |
| id | oxford-uuid:f721e44e-af9c-4ee6-bca9-995e0ebbd7f1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:16:20Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | oxford-uuid:f721e44e-af9c-4ee6-bca9-995e0ebbd7f12024-07-16T08:31:06ZRadiation response and combination target discovery in a novel model of rectal cancerThesishttp://purl.org/coar/resource_type/c_db06uuid:f721e44e-af9c-4ee6-bca9-995e0ebbd7f1Rectum--CancerRadiotherapyOncology, ExperimentalCancer--ImmunotherapyEnglishHyrax Deposit2024Beach, CJLeedham, SOlcina del Molino, MMaughan, TRyan, AHiggins, GRoxburgh, CValbuena, GBelnoue-Davis, HMulholland, E<p>Rectal cancer is typically treated with radiotherapy, with or without chemotherapy, prior to surgical resection of the tumour. However, in patients that respond poorly to radiation, tumours largely lack significant immune cells within the surrounding milieu and present with a CAF-rich stroma. We have recapitulated this radioresistant phenotype in vivo through the implantation of Apcfl/fl, KrasG12D/+, Trp53fl/fl, TgfbrIfl/fl (AKPT) organoids. Here, through the irradiation of the heterotopic AKPT model, we have identified two targets for inhibition to augment the anti-tumour effect of radiation: complement C5a receptor 1 (C5aR1) and transforming growth factor beta (TGF-β).</p> <p>We demonstrated that inhibiting C5aR1 increased the effectiveness of irradiation in the AKPT model both in vitro and in vivo. Inhibiting C5aR1 in vitro had a direct impact on tumour cell radiosensitivity in the AKPT organoid model. In vivo we demonstrated that bolstering radiation through C5aR1 inhibition acts independently to the T-cell population, as shown in athymic mice bearing AKPT tumours heterotopically. Furthermore, we hypothesise that additional effects on the macrophage and cancer-associated fibroblast (CAF) populations could contribute to the augmentation of radiation anti-tumour effects when C5aR1 is inhibited. We demonstrate an increase in the inflammatory macrophage population, as well as a shift in the CAF phenotype. Interestingly, the modest radiosensitisation observed in vitro suggest that¸ in the in vivo AKPT model, mechanisms altering the macrophage and CAF populations may be of greater importance than increased intrinsic radiosensitivity.</p> <p>We also demonstrate that the inhibition of TGF-β increased the effectiveness of radiation in vivo in the AKPT heterotopic model. Furthermore, we show that the inhibition of this multifunctional cytokine, when combined with irradiation, has a dramatic effect on both the immune cells and CAFs within the tumour milieu. These changes include a significant increase of cytotoxic T-cell infiltration of the tumour epithelium, a significant decrease in the Treg population, a shift in the macrophages toward a more inflammatory phenotype, and a shift in the CAF phenotype. These changes were reflected by the enrichment of immunogenic gene signatures in the AKPT model after treatment with radiation combined with TGF-β inhibition, with immunosuppressive signatures showing a corresponding negative enrichment. We hypothesise that the shift in the CAF population phenotype is directly linked to the increase immunogenic action against the tumour. We further suggest that in the AKPT rectal cancer model, the CAF population acts to orchestrate the sustained immune response after irradiation, provided TGF-β is inhibited.</p> |
| spellingShingle | Rectum--Cancer Radiotherapy Oncology, Experimental Cancer--Immunotherapy Beach, CJ Radiation response and combination target discovery in a novel model of rectal cancer |
| title | Radiation response and combination target discovery in a novel model of rectal cancer |
| title_full | Radiation response and combination target discovery in a novel model of rectal cancer |
| title_fullStr | Radiation response and combination target discovery in a novel model of rectal cancer |
| title_full_unstemmed | Radiation response and combination target discovery in a novel model of rectal cancer |
| title_short | Radiation response and combination target discovery in a novel model of rectal cancer |
| title_sort | radiation response and combination target discovery in a novel model of rectal cancer |
| topic | Rectum--Cancer Radiotherapy Oncology, Experimental Cancer--Immunotherapy |
| work_keys_str_mv | AT beachcj radiationresponseandcombinationtargetdiscoveryinanovelmodelofrectalcancer |