The role of immune cells in ovarian cancer
- Authors: Ahmady, Farah
- Date: 2022
- Type: Text , Thesis , PhD
- Full Text:
- Description: Ovarian cancer remains the leading cause of gynaecological disease related death in women worldwide. Patients given standard treatment have low survival rates and immunotherapy remains unsuccessful. This is largely due to the suppressive tumour microenvironment (TME) and the interaction of the different cells being poorly understood. This has sparked interest in understanding the functions of immune cells and their contribution to the TME. In chapter 3, B and T cells were characterised in samples collected from chemo-naïve highgrade serous ovarian cancer (HGSOC) patients and compared to benign and healthy controls. B cells were able to express the T cell exhaustion marker T cell immunoglobulin and mucin domain-3 (TIM-3) on their surface. Blood derived B cells of benign patients expressed less TIM-3 compared to high-grade and healthy donors. Alterations in TIM-3 expression on B cells suggests that the TME may not be causing B cells to harbour an exhaustion phenotype. The frequency of circulating mucosal-associated invariant T cells (MAIT cells) was reduced in benign and high-grade patients compared to healthy donors. Blood derived MAIT cells of healthy donors stimulated with 5-OP-RU antigen and cultured with ovarian cancer cell line supernatants had a reduced capacity of producing tumour necrosis factor (TNF)-a compared to control. The reduced frequency of MAIT cells at the premalignant state of the disease indicates that malignancy of the disease is not necessarily the contributing factor in the reduction observed. As TNF-a is a key anti-tumour cytokine expressed by MAIT cells, the impaired production may indicate defects in their function. Low dose-dense (LDD) chemotherapy has recently shown promise as depicted in a clinical study by Kannourakis et al. where LDD treated HGSOC patients had longer survival than those treated with maximum tolerated dose (MTD). It is postulated that this may be due to aspects of the immune system, however the effects of LDD chemotherapy on immune cells remains unknown. In chpter 4, circulating B and T cells of LDD treated patients were characterised and compared to untreated controls. The key finding of this study was the immunostimulatory attributes of LDD regimen in a range of B and T cell populations via their increased expression of TNF-a compared to untreated controls and healthy donors. The frequency of MAIT cells, however, was reduced in LDD treated patients, suggesting that these cells may not contribute to the immunostimulatory aspects, and that this regimen may impact their frequency by creating an environment which may not be compatible for MAIT cell survival. In chapter 5, expression of immuno-oncology protein markers in benign and high-grade primary and metastasised tumours were determined for alterations in hot and cold tumour regions using Digital Spatial Profiling (DSP). An increased expression of immune cell, costimulatory and inhibitory markers were apparent in high-grade tumours compared to benign. The stimulator of interferon genes (STING) marker was studied further, and its expression was also higher in high-grade tumours compared to benign, with cisplatin further enhancing its expression in ovarian cancer cell lines. There were alterations in the expression of some downstream molecules, however interferon (IFN)-b, the key cytokine produced in the activated STING pathway, was virtually non-existent. This suggests a defect in the pathway which if restored, may contribute to some of the known anti-tumour functions of the pathway. The results from these studies provide an understanding of differences in the immune profile of non-malignant and malignant ovarian cancer. These findings work together to improve our understanding of the unique TME with the aim to identify potential immune therapeutic targets for future study.
- Description: Doctor of Philosophy
- Authors: Ahmady, Farah
- Date: 2022
- Type: Text , Thesis , PhD
- Full Text:
- Description: Ovarian cancer remains the leading cause of gynaecological disease related death in women worldwide. Patients given standard treatment have low survival rates and immunotherapy remains unsuccessful. This is largely due to the suppressive tumour microenvironment (TME) and the interaction of the different cells being poorly understood. This has sparked interest in understanding the functions of immune cells and their contribution to the TME. In chapter 3, B and T cells were characterised in samples collected from chemo-naïve highgrade serous ovarian cancer (HGSOC) patients and compared to benign and healthy controls. B cells were able to express the T cell exhaustion marker T cell immunoglobulin and mucin domain-3 (TIM-3) on their surface. Blood derived B cells of benign patients expressed less TIM-3 compared to high-grade and healthy donors. Alterations in TIM-3 expression on B cells suggests that the TME may not be causing B cells to harbour an exhaustion phenotype. The frequency of circulating mucosal-associated invariant T cells (MAIT cells) was reduced in benign and high-grade patients compared to healthy donors. Blood derived MAIT cells of healthy donors stimulated with 5-OP-RU antigen and cultured with ovarian cancer cell line supernatants had a reduced capacity of producing tumour necrosis factor (TNF)-a compared to control. The reduced frequency of MAIT cells at the premalignant state of the disease indicates that malignancy of the disease is not necessarily the contributing factor in the reduction observed. As TNF-a is a key anti-tumour cytokine expressed by MAIT cells, the impaired production may indicate defects in their function. Low dose-dense (LDD) chemotherapy has recently shown promise as depicted in a clinical study by Kannourakis et al. where LDD treated HGSOC patients had longer survival than those treated with maximum tolerated dose (MTD). It is postulated that this may be due to aspects of the immune system, however the effects of LDD chemotherapy on immune cells remains unknown. In chpter 4, circulating B and T cells of LDD treated patients were characterised and compared to untreated controls. The key finding of this study was the immunostimulatory attributes of LDD regimen in a range of B and T cell populations via their increased expression of TNF-a compared to untreated controls and healthy donors. The frequency of MAIT cells, however, was reduced in LDD treated patients, suggesting that these cells may not contribute to the immunostimulatory aspects, and that this regimen may impact their frequency by creating an environment which may not be compatible for MAIT cell survival. In chapter 5, expression of immuno-oncology protein markers in benign and high-grade primary and metastasised tumours were determined for alterations in hot and cold tumour regions using Digital Spatial Profiling (DSP). An increased expression of immune cell, costimulatory and inhibitory markers were apparent in high-grade tumours compared to benign. The stimulator of interferon genes (STING) marker was studied further, and its expression was also higher in high-grade tumours compared to benign, with cisplatin further enhancing its expression in ovarian cancer cell lines. There were alterations in the expression of some downstream molecules, however interferon (IFN)-b, the key cytokine produced in the activated STING pathway, was virtually non-existent. This suggests a defect in the pathway which if restored, may contribute to some of the known anti-tumour functions of the pathway. The results from these studies provide an understanding of differences in the immune profile of non-malignant and malignant ovarian cancer. These findings work together to improve our understanding of the unique TME with the aim to identify potential immune therapeutic targets for future study.
- Description: Doctor of Philosophy
Tumour microenvironment and metabolic plasticity in cancer and cancer stem cells : Perspectives on metabolic and immune regulatory signatures in chemoresistant ovarian cancer stem cells
- Ahmed, Nuzhat, Escalona, Ruth, Leung, Dilys, Chan, Emily, Kannourakis, George
- Authors: Ahmed, Nuzhat , Escalona, Ruth , Leung, Dilys , Chan, Emily , Kannourakis, George
- Date: 2018
- Type: Text , Journal article , Review
- Relation: Seminars in Cancer Biology Vol. 53, no. (2018), p. 265-281
- Full Text:
- Reviewed:
- Description: Cancer stem cells (CSCs) are a sub-population of tumour cells, which are responsible to drive tumour growth, metastasis and therapy resistance. It has recently been proposed that enhanced glucose metabolism and immune evasion by tumour cells are linked, and are modulated by the changing tumour microenvironment (TME) that creates a competition for nutrient consumption between tumour and different sub-types of cells attracted to the TME. To facilitate efficient nutrient distribution, oncogene-induced inflammatory milieu in the tumours facilitate adaptive metabolic changes in the surrounding non-malignant cells to secrete metabolites that are used as alternative nutrient sources by the tumours to sustain its increasing energy needs for growth and anabolic functions. This scenario also affects CSCs residing at the primary or metastatic niches. This review summarises recent advances in our understanding of the metabolic phenotypes of cancer cells and CSCs and how these processes are affected by the TME. We also discuss how the evolving TME modulates tumour cells and CSCs in cancer progression. Using previously described proteomic and genomic platforms, ovarian cancer cell lines and a mouse xenograft model we highlight the existence of metabolic and immune regulatory signatures in chemoresistant ovarian CSCs, and discuss how these processes may affect recurrence in ovarian tumours. We propose that progress in cancer control and eradication may depend not only on the elimination of highly chemoresistant CSCs, but also in designing novel strategies which would intervene with the tumour-promoting TME factors.
- Authors: Ahmed, Nuzhat , Escalona, Ruth , Leung, Dilys , Chan, Emily , Kannourakis, George
- Date: 2018
- Type: Text , Journal article , Review
- Relation: Seminars in Cancer Biology Vol. 53, no. (2018), p. 265-281
- Full Text:
- Reviewed:
- Description: Cancer stem cells (CSCs) are a sub-population of tumour cells, which are responsible to drive tumour growth, metastasis and therapy resistance. It has recently been proposed that enhanced glucose metabolism and immune evasion by tumour cells are linked, and are modulated by the changing tumour microenvironment (TME) that creates a competition for nutrient consumption between tumour and different sub-types of cells attracted to the TME. To facilitate efficient nutrient distribution, oncogene-induced inflammatory milieu in the tumours facilitate adaptive metabolic changes in the surrounding non-malignant cells to secrete metabolites that are used as alternative nutrient sources by the tumours to sustain its increasing energy needs for growth and anabolic functions. This scenario also affects CSCs residing at the primary or metastatic niches. This review summarises recent advances in our understanding of the metabolic phenotypes of cancer cells and CSCs and how these processes are affected by the TME. We also discuss how the evolving TME modulates tumour cells and CSCs in cancer progression. Using previously described proteomic and genomic platforms, ovarian cancer cell lines and a mouse xenograft model we highlight the existence of metabolic and immune regulatory signatures in chemoresistant ovarian CSCs, and discuss how these processes may affect recurrence in ovarian tumours. We propose that progress in cancer control and eradication may depend not only on the elimination of highly chemoresistant CSCs, but also in designing novel strategies which would intervene with the tumour-promoting TME factors.
Polyclonal T-Cells Express CD1a in Langerhans Cell Histiocytosis (LCH) Lesions
- West, Jennifer, Olsen, Sharon, Mitchell, Jenée, Priddle, Ross, Luke, Jennifer, Åkefeldt, Selma Olsson, Henter, Jan-Inge, Turville, Christopher, Kannourakis, George
- Authors: West, Jennifer , Olsen, Sharon , Mitchell, Jenée , Priddle, Ross , Luke, Jennifer , Åkefeldt, Selma Olsson , Henter, Jan-Inge , Turville, Christopher , Kannourakis, George
- Date: 2014
- Type: Text , Journal article
- Relation: PLoS ONE Vol. 9, no. 10 (2014), p. 1-12
- Full Text:
- Reviewed:
- Description: Langerhans cell histiocytosis (LCH) is a complex and poorly understood disorder that has characteristics of both inflammatory and neoplastic disease. By using eight-colour flow cytometry, we have identified a previously unreported population of CD1a+/CD3+ T-cells in LCH lesions. The expression of CD1a is regarded as a hallmark of this disease; however, it has always been presumed that it was only expressed by pathogenic Langerhans cells (LCs). We have now detected CD1a expression by a range of T-cell subsets within all of the LCH lesions that were examined, establishing that CD1a expression in these lesions is no longer restricted to pathogenic LCs. The presence of CD1a+ T-cells in all of the LCH lesions that we have studied to date warrants further investigation into their biological function to determine whether these cells are important in the pathogenesis of LCH. [ABSTRACT FROM AUTHOR] Copyright of PLoS ONE is the property of Public Library of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Authors: West, Jennifer , Olsen, Sharon , Mitchell, Jenée , Priddle, Ross , Luke, Jennifer , Åkefeldt, Selma Olsson , Henter, Jan-Inge , Turville, Christopher , Kannourakis, George
- Date: 2014
- Type: Text , Journal article
- Relation: PLoS ONE Vol. 9, no. 10 (2014), p. 1-12
- Full Text:
- Reviewed:
- Description: Langerhans cell histiocytosis (LCH) is a complex and poorly understood disorder that has characteristics of both inflammatory and neoplastic disease. By using eight-colour flow cytometry, we have identified a previously unreported population of CD1a+/CD3+ T-cells in LCH lesions. The expression of CD1a is regarded as a hallmark of this disease; however, it has always been presumed that it was only expressed by pathogenic Langerhans cells (LCs). We have now detected CD1a expression by a range of T-cell subsets within all of the LCH lesions that were examined, establishing that CD1a expression in these lesions is no longer restricted to pathogenic LCs. The presence of CD1a+ T-cells in all of the LCH lesions that we have studied to date warrants further investigation into their biological function to determine whether these cells are important in the pathogenesis of LCH. [ABSTRACT FROM AUTHOR] Copyright of PLoS ONE is the property of Public Library of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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