The characterization of macrophages in melanoma and the effect of electroporation on melanoma conditioned macrophages

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dc.contributor.advisor Forde, Patrick en
dc.contributor.advisor Heffron, Cynthia en Tremble, Liam Friel 2020-01-20T12:35:10Z 2019 2019
dc.identifier.citation Tremble, L. F. 2019. The characterization of macrophages in melanoma and the effect of electroporation on melanoma conditioned macrophages. PhD Thesis, University College Cork. en
dc.identifier.endpage 210 en
dc.description.abstract Approximately 11,000 people are diagnosed with skin cancer in Ireland every year and approximately 1,000 of these present with malignant melanoma. Due to lifestyle changes and an increase in UV exposure, incidences are expected to continue to rise despite the presence of health campaigns. Immune cells, called macrophages, have been documented to represent up to 50% of the tumour mass in some melanomas. However, we have only a nascent understanding of the role of these cells in tumour biology and treatment responses. One treatment offered to advanced melanoma patients is electrochemotherapy, which has exceptionally high complete local response rates of up to 80%, and is under investigation with the replacement of chemotherapy with non-cytotoxic drugs such as calcium. Calcium electroporation has shown the ability to induce comparable response rates and is under increased scrutiny due to the presence of a case report in which a systemic anti-melanoma response was seen following treatment. While the effect of electroporation, and increasingly, calcium electroporation on tumour cells has been well documented. The effect of these treatments on bystander cells in the treatment area, such as tumour-associated macrophages, has not been investigated. Here we present clinical findings of the presence of distinct macrophage populations recruited to melanoma tissue. Using their inflammatory phenotype, effect on gene expression within the tumour, and correlation with survival outcomes we give compelling evidence that melanomas contain distinct populations of both active, and relatively inactive macrophages, which can vary depending on the pathological features of the tumour, such as Breslow depth and BRAF mutational status. Given the presence of an inflammatory population of macrophages in the tumour, we sought to develop an in vitro model in which we could examine the effect of electroporation on melanoma conditioned macrophages. Using an adapted model of bone marrow-derived monocyte development followed by melanoma conditioning, we were able to generate an immunologically active model of melanoma conditioned monocytes, which upregulated M2-associated surface receptors, similar to the predominant population of intratumoural macrophages. These conditioned cells showed no major increase in inducible nitric oxide synthase or arginase expression, as was seen clinically, but were able to affect T cell proliferation and polarization, indicating an influential immunological phenotype. In chapter 5, we investigate the effect of electroporation on these cells, and show that, similarly to tumour cells, their membranes do become reversibly electroporated. Using the parameters investigated in chapter 4 we show that calcium electroporation does impact their phenotype and functionality, and critically, influences their ability to subsequently activate and polarize T cells. Our data indicate that electroporation does not deplete intratumoural macrophages or inhibit their ability to drive cytotoxic T cell responses, suggesting that, from a macrophage perspective, calcium electroporation may be complementary to other immunogenic treatments. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2019, Liam Friel Tremble. en
dc.rights.uri en
dc.subject Cancer en
dc.subject Melanoma en
dc.subject Immunology en
dc.subject Macrophage en
dc.title The characterization of macrophages in melanoma and the effect of electroporation on melanoma conditioned macrophages en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD en
dc.internal.availability Full text not available en Restricted to everyone for one year en 2021-01-19T12:35:10Z
dc.description.version Accepted Version
dc.contributor.funder Breakthrough Cancer Research en
dc.description.status Not peer reviewed en Surgery en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out No en
dc.thesis.opt-out false
dc.check.entireThesis Entire Thesis Restricted
dc.check.embargoformat Apply the embargo to the e-thesis on CORA (If you have submitted an e-thesis and want to embargo it on CORA) en
dc.internal.conferring Spring 2020 en
dc.internal.ricu Cork Cancer Research Centre en

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