Investigating the effects of IGFs on immune responses in prostate cancer
<p>Prostate cancer is the second most common cancer in men. Insulin-like growth factor (IGF), a hormone necessary for normal cell growth, is correlated with prostate cancer progression and mortality and is known to have immunosuppressive actions in the tumour immune-microenvironment (TIME). Th...
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| Format: | Thesis |
| Language: | English |
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2024
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| _version_ | 1824458871744233472 |
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| author | Kim, J |
| author2 | Macaulay, V |
| author_facet | Macaulay, V Kim, J |
| author_sort | Kim, J |
| collection | OXFORD |
| description | <p>Prostate cancer is the second most common cancer in men. Insulin-like growth factor (IGF), a hormone necessary for normal cell growth, is correlated with prostate cancer progression and mortality and is known to have immunosuppressive actions in the tumour immune-microenvironment (TIME). The objective of the project was to investigate immune-modulatory impact of IGF signalling in prostate cancer <em>in vitro</em> and in patients. The first aim was to test the effects of IGF blockade in prostate cancer by exploring the effects of IGF blocking monoclonal antibody xentuzumab <em>in vitro</em> and <em>in vivo</em>, alone and in combination with anti-PD-1 immunotherapy. Xentuzumab treatment successfully inhibited IGF axis activation <em>in vitro</em> and changed T cell and macrophage effects and infiltration <em>in vivo</em>. Secondly, effects of IGFs on macrophage phenotype and phagocytic function were characterised <em>in vitro</em>. Xentuzumab treatment reduced tumour-promoting M2 macrophages, increased phagocytosis of cancer cells by pro-inflammatory M1 macrophages, and enhanced T cell activity. The last aim was to understand the impact of IGF blockade on localised prostate cancer TIME in the windows trial set-up (NCT05110495). In addition to successfully blocking IGF axis (primary endpoint) and confirming its safety and tolerability (secondary endpoint), xentuzumab treatment significantly increased CD8+ T cell infiltration and reduced serum IGF bioactivity, Ki67+ tumour proliferation, AR+ epithelium, and Treg subtypes. RNA sequencing of the tumours revealed inflammatory and senescence-associated secretory phenotype (SASP)-like signatures, suggesting cellular stress caused by the IGF axis blockade. In conclusion, IGF axis contributes to remodelling of prostate cancer TIME, with species-dependent changes in immune cell repertoire. Provided we learn more about the nature of this immune remodelling, this thesis presents therapeutic potential of xentuzumab to be used as an adjuvant therapy in combination with immune intervention.</p> |
| first_indexed | 2025-02-19T04:32:47Z |
| format | Thesis |
| id | oxford-uuid:2eacb003-066e-4d0a-aa10-f400e36a186c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:32:47Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | oxford-uuid:2eacb003-066e-4d0a-aa10-f400e36a186c2025-01-17T16:59:31ZInvestigating the effects of IGFs on immune responses in prostate cancerThesishttp://purl.org/coar/resource_type/c_db06uuid:2eacb003-066e-4d0a-aa10-f400e36a186cEnglishHyrax Deposit2024Kim, JMacaulay, VMills, ILamb, A<p>Prostate cancer is the second most common cancer in men. Insulin-like growth factor (IGF), a hormone necessary for normal cell growth, is correlated with prostate cancer progression and mortality and is known to have immunosuppressive actions in the tumour immune-microenvironment (TIME). The objective of the project was to investigate immune-modulatory impact of IGF signalling in prostate cancer <em>in vitro</em> and in patients. The first aim was to test the effects of IGF blockade in prostate cancer by exploring the effects of IGF blocking monoclonal antibody xentuzumab <em>in vitro</em> and <em>in vivo</em>, alone and in combination with anti-PD-1 immunotherapy. Xentuzumab treatment successfully inhibited IGF axis activation <em>in vitro</em> and changed T cell and macrophage effects and infiltration <em>in vivo</em>. Secondly, effects of IGFs on macrophage phenotype and phagocytic function were characterised <em>in vitro</em>. Xentuzumab treatment reduced tumour-promoting M2 macrophages, increased phagocytosis of cancer cells by pro-inflammatory M1 macrophages, and enhanced T cell activity. The last aim was to understand the impact of IGF blockade on localised prostate cancer TIME in the windows trial set-up (NCT05110495). In addition to successfully blocking IGF axis (primary endpoint) and confirming its safety and tolerability (secondary endpoint), xentuzumab treatment significantly increased CD8+ T cell infiltration and reduced serum IGF bioactivity, Ki67+ tumour proliferation, AR+ epithelium, and Treg subtypes. RNA sequencing of the tumours revealed inflammatory and senescence-associated secretory phenotype (SASP)-like signatures, suggesting cellular stress caused by the IGF axis blockade. In conclusion, IGF axis contributes to remodelling of prostate cancer TIME, with species-dependent changes in immune cell repertoire. Provided we learn more about the nature of this immune remodelling, this thesis presents therapeutic potential of xentuzumab to be used as an adjuvant therapy in combination with immune intervention.</p> |
| spellingShingle | Kim, J Investigating the effects of IGFs on immune responses in prostate cancer |
| title | Investigating the effects of IGFs on immune responses in prostate cancer |
| title_full | Investigating the effects of IGFs on immune responses in prostate cancer |
| title_fullStr | Investigating the effects of IGFs on immune responses in prostate cancer |
| title_full_unstemmed | Investigating the effects of IGFs on immune responses in prostate cancer |
| title_short | Investigating the effects of IGFs on immune responses in prostate cancer |
| title_sort | investigating the effects of igfs on immune responses in prostate cancer |
| work_keys_str_mv | AT kimj investigatingtheeffectsofigfsonimmuneresponsesinprostatecancer |