An emerging role for immune regulatory subsets in chronic lymphocytic leukaemia
- Wallace, Morgan, Alcantara, Marice, Minoda, Yosuke, Kannourakis, George, Berzins, Stuart
- Authors: Wallace, Morgan , Alcantara, Marice , Minoda, Yosuke , Kannourakis, George , Berzins, Stuart
- Date: 2015
- Type: Text , Journal article
- Relation: International Immunopharmacology Vol. 28, no. 2 (2015), p. 897-900
- Full Text: false
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- Description: The last few years has seen the burgeoning of a new category of therapeutics for cancer targeting immune regulatory pathways. Antibodies that block the PD-1/PD-L1 interaction are perhaps the most prominent of these new anti-cancer therapies, but several other inhibitory receptor ligand interactions have also shown promise as targets in clinical trials, including CTLA-4/CD80 and Lag-3/MHC class II. Related to this is a rapidly improving knowledge of 'regulatory' lymphocyte lineages, including NKT cells, MATT cells, B regulatory cells and others. These cells have potent cytokine responses that can influence the functioning of other immune cells and many researchers believe that they could be effective targets for therapies designed to enhance immune responses to cancer. This review will outline our current understanding of FOXP3 + 'Tregs', NKT cells, MAIT cells and B regulatory cells immune regulatory cell populations in cancer, with a particular focus on chronic lymphocytic leukaemia (CLL). We will discuss evidence linking CLL with immune regulatory dysfunction and the potential for new therapies targeting regulatory cells. (C) 2015 Elsevier B.V. All rights reserved.
Experimental and human evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin NGAL ) in the development of cardiac hypertrophy and heart failure
- Marques, Francine, Prestes, Priscilla, Byars, Sean, Ritchie, Scott, Wurtz, Peter, Patel, Sheila, Booth, Scott, Rana, Indrajeetsinh, Minoda, Yosuke, Berzins, Stuart, Curl, Claire, Bell, James, Wai, Bryan, Srivastava, Piyush, Kangas, Antti, Soininen, Pasi, Ruohonen, Saku, Kahonen, Mika, Lehtimaki, Terho, Raitoharju, Emma, Havulinna, Aki, Perola, Markus, Raitakari, Olli, Salomaa, Veikko, Ala-Korpela, Mika, Kettunen, Johannes, McGlynn, Maree, Kelly, Jason, Wlodek, Mary, Lewandowski, Paul, Delbridge, Lea, Burrell, Louise, Inouye, Michael, Harrap, Stephen, Charchar, Fadi
- Authors: Marques, Francine , Prestes, Priscilla , Byars, Sean , Ritchie, Scott , Wurtz, Peter , Patel, Sheila , Booth, Scott , Rana, Indrajeetsinh , Minoda, Yosuke , Berzins, Stuart , Curl, Claire , Bell, James , Wai, Bryan , Srivastava, Piyush , Kangas, Antti , Soininen, Pasi , Ruohonen, Saku , Kahonen, Mika , Lehtimaki, Terho , Raitoharju, Emma , Havulinna, Aki , Perola, Markus , Raitakari, Olli , Salomaa, Veikko , Ala-Korpela, Mika , Kettunen, Johannes , McGlynn, Maree , Kelly, Jason , Wlodek, Mary , Lewandowski, Paul , Delbridge, Lea , Burrell, Louise , Inouye, Michael , Harrap, Stephen , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Journal of the American Heart Association Vol. 6, no. 6 (2017), p. 1-58
- Relation: http://purl.org/au-research/grants/nhmrc/1034371
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- Description: Background-Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. Methods and Results-We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. Conclusions-Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.
- Authors: Marques, Francine , Prestes, Priscilla , Byars, Sean , Ritchie, Scott , Wurtz, Peter , Patel, Sheila , Booth, Scott , Rana, Indrajeetsinh , Minoda, Yosuke , Berzins, Stuart , Curl, Claire , Bell, James , Wai, Bryan , Srivastava, Piyush , Kangas, Antti , Soininen, Pasi , Ruohonen, Saku , Kahonen, Mika , Lehtimaki, Terho , Raitoharju, Emma , Havulinna, Aki , Perola, Markus , Raitakari, Olli , Salomaa, Veikko , Ala-Korpela, Mika , Kettunen, Johannes , McGlynn, Maree , Kelly, Jason , Wlodek, Mary , Lewandowski, Paul , Delbridge, Lea , Burrell, Louise , Inouye, Michael , Harrap, Stephen , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Journal of the American Heart Association Vol. 6, no. 6 (2017), p. 1-58
- Relation: http://purl.org/au-research/grants/nhmrc/1034371
- Full Text:
- Reviewed:
- Description: Background-Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. Methods and Results-We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. Conclusions-Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.
Innate-like T cells in patients with cancer
- Authors: Minoda, Yosuke
- Date: 2017
- Type: Text , Thesis , PhD
- Full Text:
- Description: Innate-like T cells, including invariant natural killer T (NKT), mucosal associated invariant T (MAIT) cells or g T cells are associated with regulation of anti-tumour responses in humans and mice, although their exact role remains controversial. We have studied innate-like T cells from tumour infiltrating lymphocytes (TILS), peripheral blood mononuclear cells (PBMCs) and bone marrow (BM) derived cells from patients undergoing treatment for cancer and compared their characteristics to cells from healthy donors. We identifed that the overall frequency of innate-like T cells was variably deficient in patients with blood or solid cancers. Interestingly, the deficiency of innate-like T cells appeared to be more severe than that of other T cells suggesting a specific impact. An increased proportion of activated g T cells and MAIT cells suggested they could have a functional role in responses to cancer cells. Despite the deficiency of these subsets in patient tissue samples, we showed that anti-tumour capacity of innate-like T cells was intact as innate-like T cells in most patient groups had a similar cytokine response to stimulation as cells from healthy donors. Finally, we also showed that innate-like T cells appeared not to broadly recognize cancer cells, as no direct impact was identified in their overall frequency or cytokine expression when exposed to autologous tumour cells, cancer lysates or lipids extracted from patient tumours, or colorectal cancer cell lines. This project was aimed at providing an overview of potential defects in innate-like T cells based on my analysis of a wide range of samples in the Fiona Elsey Cancer Research Institute (FECRI) Tissue Bank. As a result of my studies, we have established a clear understanding of innate cells in cancer, which provides a basis for future studies. Our novel findings include analysis of frequency distribution and functional capacity of MAIT cells in solid tumours other than colorectal cancer and in patients with blood cancers such as chronic lymphocytic leukaemia (CLL), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM) or other haematological malignancies, something not previously reported. Taken together, we showed that a deficiency of innate-like T cells is common in patient groups with cancer and could be a risk factor for disease and possibly a target for immunotherapies, but the functional capacity was intact for cytokine responses.
- Description: Doctor of Philosophy
- Description: Innate-like T cells, including invariant natural killer T (NKT), mucosal associated invariant T (MAIT) cells or
- Authors: Minoda, Yosuke
- Date: 2017
- Type: Text , Thesis , PhD
- Full Text:
- Description: Innate-like T cells, including invariant natural killer T (NKT), mucosal associated invariant T (MAIT) cells or g T cells are associated with regulation of anti-tumour responses in humans and mice, although their exact role remains controversial. We have studied innate-like T cells from tumour infiltrating lymphocytes (TILS), peripheral blood mononuclear cells (PBMCs) and bone marrow (BM) derived cells from patients undergoing treatment for cancer and compared their characteristics to cells from healthy donors. We identifed that the overall frequency of innate-like T cells was variably deficient in patients with blood or solid cancers. Interestingly, the deficiency of innate-like T cells appeared to be more severe than that of other T cells suggesting a specific impact. An increased proportion of activated g T cells and MAIT cells suggested they could have a functional role in responses to cancer cells. Despite the deficiency of these subsets in patient tissue samples, we showed that anti-tumour capacity of innate-like T cells was intact as innate-like T cells in most patient groups had a similar cytokine response to stimulation as cells from healthy donors. Finally, we also showed that innate-like T cells appeared not to broadly recognize cancer cells, as no direct impact was identified in their overall frequency or cytokine expression when exposed to autologous tumour cells, cancer lysates or lipids extracted from patient tumours, or colorectal cancer cell lines. This project was aimed at providing an overview of potential defects in innate-like T cells based on my analysis of a wide range of samples in the Fiona Elsey Cancer Research Institute (FECRI) Tissue Bank. As a result of my studies, we have established a clear understanding of innate cells in cancer, which provides a basis for future studies. Our novel findings include analysis of frequency distribution and functional capacity of MAIT cells in solid tumours other than colorectal cancer and in patients with blood cancers such as chronic lymphocytic leukaemia (CLL), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM) or other haematological malignancies, something not previously reported. Taken together, we showed that a deficiency of innate-like T cells is common in patient groups with cancer and could be a risk factor for disease and possibly a target for immunotherapies, but the functional capacity was intact for cytokine responses.
- Description: Doctor of Philosophy
- Description: Innate-like T cells, including invariant natural killer T (NKT), mucosal associated invariant T (MAIT) cells or
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