Abstract

Decitabine is a DNA-hypomethylating agent that has been widely applied for the treatment of acute myeloid leukaemia (AML) patients who are elderly or unfit for intensive therapy. Although effective, the complete response rate to decitabine is only around 30% and the overall survival remains poor. Emerging data support that regulation of DNA methylation is critical to control immune cell development, differentiation and activation. We hypothesize that defining how decitabine influences the immune responses in AML will facilitate the development of novel immune-based leukaemia therapeutics. Here, we performed phenotypic and functional immune analysis on clinical samples from AML patients receiving decitabine treatment and demonstrated a significant impact of decitabine on the immune system. T-cell expression of inhibitory molecules was upregulated and the ability of CD8 T cells to produce cytokines was decreased upon decitabine treatment. Importantly, in an unbiased comprehensive analysis, we identified a unique immune signature containing a cluster of key immune markers that clearly separate patients who achieved complete remission after decitabine from those who failed to do so. Therefore, this immune signature has a strong predictive value for clinical response. Collectively, our study suggests that immune-based analyses may predict clinical response to decitabine and provide a therapeutic strategy to improve the treatment of AML.

Original languageEnglish (US)
JournalBritish Journal of Haematology
DOIs
StateAccepted/In press - Jan 1 2019

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decitabine
Acute Myeloid Leukemia
Therapeutics
T-Lymphocytes
DNA Methylation

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

@article{2eb0af45e6254bcb960d10b538fcee07,
title = "Multi-dimensional analysis identifies an immune signature predicting response to decitabine treatment in elderly patients with AML",
abstract = "Decitabine is a DNA-hypomethylating agent that has been widely applied for the treatment of acute myeloid leukaemia (AML) patients who are elderly or unfit for intensive therapy. Although effective, the complete response rate to decitabine is only around 30{\%} and the overall survival remains poor. Emerging data support that regulation of DNA methylation is critical to control immune cell development, differentiation and activation. We hypothesize that defining how decitabine influences the immune responses in AML will facilitate the development of novel immune-based leukaemia therapeutics. Here, we performed phenotypic and functional immune analysis on clinical samples from AML patients receiving decitabine treatment and demonstrated a significant impact of decitabine on the immune system. T-cell expression of inhibitory molecules was upregulated and the ability of CD8 T cells to produce cytokines was decreased upon decitabine treatment. Importantly, in an unbiased comprehensive analysis, we identified a unique immune signature containing a cluster of key immune markers that clearly separate patients who achieved complete remission after decitabine from those who failed to do so. Therefore, this immune signature has a strong predictive value for clinical response. Collectively, our study suggests that immune-based analyses may predict clinical response to decitabine and provide a therapeutic strategy to improve the treatment of AML.",
author = "Chenchen Zhao and Bei Jia and Ming Wang and Schell, {Todd D.} and Claxton, {David F.} and Ehmann, {W. Christopher} and Rybka, {Witold B.} and Shin Mineishi and Seema Naik and Natthapol Songdej and Sivik, {Jeff M.} and Hohl, {Raymond J.} and Hui Zeng and Hong Zheng",
year = "2019",
month = "1",
day = "1",
doi = "10.1111/bjh.16228",
language = "English (US)",
journal = "British Journal of Haematology",
issn = "0007-1048",
publisher = "Wiley-Blackwell",

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T1 - Multi-dimensional analysis identifies an immune signature predicting response to decitabine treatment in elderly patients with AML

AU - Zhao, Chenchen

AU - Jia, Bei

AU - Wang, Ming

AU - Schell, Todd D.

AU - Claxton, David F.

AU - Ehmann, W. Christopher

AU - Rybka, Witold B.

AU - Mineishi, Shin

AU - Naik, Seema

AU - Songdej, Natthapol

AU - Sivik, Jeff M.

AU - Hohl, Raymond J.

AU - Zeng, Hui

AU - Zheng, Hong

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Decitabine is a DNA-hypomethylating agent that has been widely applied for the treatment of acute myeloid leukaemia (AML) patients who are elderly or unfit for intensive therapy. Although effective, the complete response rate to decitabine is only around 30% and the overall survival remains poor. Emerging data support that regulation of DNA methylation is critical to control immune cell development, differentiation and activation. We hypothesize that defining how decitabine influences the immune responses in AML will facilitate the development of novel immune-based leukaemia therapeutics. Here, we performed phenotypic and functional immune analysis on clinical samples from AML patients receiving decitabine treatment and demonstrated a significant impact of decitabine on the immune system. T-cell expression of inhibitory molecules was upregulated and the ability of CD8 T cells to produce cytokines was decreased upon decitabine treatment. Importantly, in an unbiased comprehensive analysis, we identified a unique immune signature containing a cluster of key immune markers that clearly separate patients who achieved complete remission after decitabine from those who failed to do so. Therefore, this immune signature has a strong predictive value for clinical response. Collectively, our study suggests that immune-based analyses may predict clinical response to decitabine and provide a therapeutic strategy to improve the treatment of AML.

AB - Decitabine is a DNA-hypomethylating agent that has been widely applied for the treatment of acute myeloid leukaemia (AML) patients who are elderly or unfit for intensive therapy. Although effective, the complete response rate to decitabine is only around 30% and the overall survival remains poor. Emerging data support that regulation of DNA methylation is critical to control immune cell development, differentiation and activation. We hypothesize that defining how decitabine influences the immune responses in AML will facilitate the development of novel immune-based leukaemia therapeutics. Here, we performed phenotypic and functional immune analysis on clinical samples from AML patients receiving decitabine treatment and demonstrated a significant impact of decitabine on the immune system. T-cell expression of inhibitory molecules was upregulated and the ability of CD8 T cells to produce cytokines was decreased upon decitabine treatment. Importantly, in an unbiased comprehensive analysis, we identified a unique immune signature containing a cluster of key immune markers that clearly separate patients who achieved complete remission after decitabine from those who failed to do so. Therefore, this immune signature has a strong predictive value for clinical response. Collectively, our study suggests that immune-based analyses may predict clinical response to decitabine and provide a therapeutic strategy to improve the treatment of AML.

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