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Modulation of indoleamine 2, 3-dioxygenase 1 expression by activated T-cells in breast cancer is controlled by epigenetic mechanisms.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
書名/作者:	Modulation of indoleamine 2, 3-dioxygenase 1 expression by activated T-cells in breast cancer is controlled by epigenetic mechanisms.
作者:	Noonepalle, Satish Kumar Reddy.
面頁冊數:	131 p.
附註:	Source: Dissertation Abstracts International, Volume: 77-03(E), Section: B.
Contained By:	Dissertation Abstracts International77-03B(E).
標題:	Biochemistry.
標題:	Biology.
ISBN:	9781339157405
摘要、提要註:	Tumor infiltrating lymphocytes (TILs) secrete cytokines that modulate immune responses at tumor microenvironment. Tumor suppressor activity of cytokines such as interferon gamma (IFNgamma) also activate expression of immune suppressive factors such as IDO and PD-L1 in tumor cells. However, there is still much to learn about how tumor cells counter the immune cells at gene expression level. In this study, RNA-seq analysis of breast cancer cells after in-vitro co-culture with anti-CD3/CD28 activated human T-cells revealed that IFNgamma induced immune response gene signature is common to both triple negative breast cancer (TNBC) MDA-MB-231 and estrogen receptor positive (ER+) MCF7 cells. However, IDO1 expression was differentially upregulated with significantly higher expression in MDA-MB-231 compared to MCF7 cells. Analysis of TCGA breast cancer datasets revealed subtype-specific mRNA expression and IDO1 promoter DNA methylation. We observed that IDO1 mRNA expression and promoter methylation followed inverse correlation. TNBC/basal subtype was hypomethylated at IDO1 promoter with higher mRNA expression compared to ER+ subtype that was hypermethylated with relatively lower IDO1 mRNA expression. IDO1 promoter methylation was confirmed by pyrosequencing analysis of a panel of breast cancer cell lines and patient tumors. IFNgamma treatment of MDA-MB-231 and MCF7 breast cancer cells revealed no difference in terms of upstream signaling and IDO1 mRNA stability. Treatment with demethylating agent, 5-aza-deoxycytidine, synergistically up-regulated IDO1 mRNA expression in ER+ MCF7 cells highlighting that CpG methylation controls IDO1 gene expression. We also found positive correlation between IDO1 and CD8A expression and their association with better relapse free survival in TNBC/basal subtype patients suggesting that IDO1 expression is driven by intrinsic immune surveillance of TILs. These findings provide evidence that IDO1 promoter methylation regulates anti-immune responses by tumor cells towards TILs and it could be used as predictive biomarker for IDO inhibitor-based immunotherapy of breast cancer.
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3729786

Modulation of indoleamine 2, 3-dioxygenase 1 expression by activated T-cells in breast cancer is controlled by epigenetic mechanisms.
Noonepalle, Satish Kumar Reddy.

Modulation of indoleamine 2, 3-dioxygenase 1 expression by activated T-cells in breast cancer is controlled by epigenetic mechanisms. - 131 p.

Source: Dissertation Abstracts International, Volume: 77-03(E), Section: B.

Thesis (Ph.D.)--Georgia Regents University, 2016.

Tumor infiltrating lymphocytes (TILs) secrete cytokines that modulate immune responses at tumor microenvironment. Tumor suppressor activity of cytokines such as interferon gamma (IFNgamma) also activate expression of immune suppressive factors such as IDO and PD-L1 in tumor cells. However, there is still much to learn about how tumor cells counter the immune cells at gene expression level. In this study, RNA-seq analysis of breast cancer cells after in-vitro co-culture with anti-CD3/CD28 activated human T-cells revealed that IFNgamma induced immune response gene signature is common to both triple negative breast cancer (TNBC) MDA-MB-231 and estrogen receptor positive (ER+) MCF7 cells. However, IDO1 expression was differentially upregulated with significantly higher expression in MDA-MB-231 compared to MCF7 cells. Analysis of TCGA breast cancer datasets revealed subtype-specific mRNA expression and IDO1 promoter DNA methylation. We observed that IDO1 mRNA expression and promoter methylation followed inverse correlation. TNBC/basal subtype was hypomethylated at IDO1 promoter with higher mRNA expression compared to ER+ subtype that was hypermethylated with relatively lower IDO1 mRNA expression. IDO1 promoter methylation was confirmed by pyrosequencing analysis of a panel of breast cancer cell lines and patient tumors. IFNgamma treatment of MDA-MB-231 and MCF7 breast cancer cells revealed no difference in terms of upstream signaling and IDO1 mRNA stability. Treatment with demethylating agent, 5-aza-deoxycytidine, synergistically up-regulated IDO1 mRNA expression in ER+ MCF7 cells highlighting that CpG methylation controls IDO1 gene expression. We also found positive correlation between IDO1 and CD8A expression and their association with better relapse free survival in TNBC/basal subtype patients suggesting that IDO1 expression is driven by intrinsic immune surveillance of TILs. These findings provide evidence that IDO1 promoter methylation regulates anti-immune responses by tumor cells towards TILs and it could be used as predictive biomarker for IDO inhibitor-based immunotherapy of breast cancer.

ISBN: 9781339157405Subjects--Topical Terms:

183428
Biochemistry.

Modulation of indoleamine 2, 3-dioxygenase 1 expression by activated T-cells in breast cancer is controlled by epigenetic mechanisms.
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