Decitabine-Mediated Epigenetic Reprograming Enhances Anti-leukemia Efficacy of CD123-Targeted Chimeric Antigen Receptor T-Cells
Chimeric antigen receptor (CAR) T cells represent a potentially curative therapy for patients with advanced hematological cancers; however, uncertainties surround the cell-intrinsic fitness as well as the exhaustion that restrict the capacity of CAR-T. Decitabine (DAC), a DNA demethylating agent, has been demonstrated to reverse exhaustion-associated DNA-methylation programs and to improve T cell responses against tumors. Here we show that DAC significantly enhances antileukemia functions of CD123 CAR-T cells in vitro and in vivo. Additionally, it inhibits the expression of DMNT3a and DNMT1. Using the Illumina Methylation EPIC BeadChip (850 K), we identified differentially methylated regions, most of which undergo hypomethylated changes. Transcriptomic profiling revealed that CD123 CAR-T cells treated with DAC were enriched in genes associated with naive, early memory T cells, as well as non-exhausted T cells. DAC treatment also results in upregulation of immune synapse-related genes. Finally, our data further suggest that DAC works through the regulation of cellular differentiation characterized by naive and memory phenotypes. Taken together, these findings demonstrate that DAC improves the anti-leukemia properties of CD123-directed CAR-T cells, and provides a basis for rational combinatorial CAR-T-based immunotherapy for patients with acute myeloid leukemia (AML)..
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2020 |
---|---|
Erschienen: |
2020 |
Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
---|---|
Enthalten in: |
Frontiers in Immunology - 11(2020) |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Liangshun You [VerfasserIn] |
---|
Links: |
doi.org [kostenfrei] |
---|
Themen: |
Acute myeloid leukemia |
---|
doi: |
10.3389/fimmu.2020.01787 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
DOAJ041933133 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | DOAJ041933133 | ||
003 | DE-627 | ||
005 | 20230308053649.0 | ||
007 | cr uuu---uuuuu | ||
008 | 230227s2020 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.3389/fimmu.2020.01787 |2 doi | |
035 | |a (DE-627)DOAJ041933133 | ||
035 | |a (DE-599)DOAJ4973f52380d84a0f881b7c8192f60106 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
050 | 0 | |a RC581-607 | |
100 | 0 | |a Liangshun You |e verfasserin |4 aut | |
245 | 1 | 0 | |a Decitabine-Mediated Epigenetic Reprograming Enhances Anti-leukemia Efficacy of CD123-Targeted Chimeric Antigen Receptor T-Cells |
264 | 1 | |c 2020 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a Computermedien |b c |2 rdamedia | ||
338 | |a Online-Ressource |b cr |2 rdacarrier | ||
520 | |a Chimeric antigen receptor (CAR) T cells represent a potentially curative therapy for patients with advanced hematological cancers; however, uncertainties surround the cell-intrinsic fitness as well as the exhaustion that restrict the capacity of CAR-T. Decitabine (DAC), a DNA demethylating agent, has been demonstrated to reverse exhaustion-associated DNA-methylation programs and to improve T cell responses against tumors. Here we show that DAC significantly enhances antileukemia functions of CD123 CAR-T cells in vitro and in vivo. Additionally, it inhibits the expression of DMNT3a and DNMT1. Using the Illumina Methylation EPIC BeadChip (850 K), we identified differentially methylated regions, most of which undergo hypomethylated changes. Transcriptomic profiling revealed that CD123 CAR-T cells treated with DAC were enriched in genes associated with naive, early memory T cells, as well as non-exhausted T cells. DAC treatment also results in upregulation of immune synapse-related genes. Finally, our data further suggest that DAC works through the regulation of cellular differentiation characterized by naive and memory phenotypes. Taken together, these findings demonstrate that DAC improves the anti-leukemia properties of CD123-directed CAR-T cells, and provides a basis for rational combinatorial CAR-T-based immunotherapy for patients with acute myeloid leukemia (AML). | ||
650 | 4 | |a decitabine | |
650 | 4 | |a CAR-T immunotherapy | |
650 | 4 | |a DNA-methylation | |
650 | 4 | |a acute myeloid leukemia | |
650 | 4 | |a T cell subsets | |
650 | 4 | |a immune synapse | |
653 | 0 | |a Immunologic diseases. Allergy | |
700 | 0 | |a Liangshun You |e verfasserin |4 aut | |
700 | 0 | |a Liangshun You |e verfasserin |4 aut | |
700 | 0 | |a Qingmei Han |e verfasserin |4 aut | |
700 | 0 | |a Qingmei Han |e verfasserin |4 aut | |
700 | 0 | |a Li Zhu |e verfasserin |4 aut | |
700 | 0 | |a Yijing Zhu |e verfasserin |4 aut | |
700 | 0 | |a Changqian Bao |e verfasserin |4 aut | |
700 | 0 | |a Changqian Bao |e verfasserin |4 aut | |
700 | 0 | |a Chunmei Yang |e verfasserin |4 aut | |
700 | 0 | |a Chunmei Yang |e verfasserin |4 aut | |
700 | 0 | |a Chunmei Yang |e verfasserin |4 aut | |
700 | 0 | |a Wen Lei |e verfasserin |4 aut | |
700 | 0 | |a Wen Lei |e verfasserin |4 aut | |
700 | 0 | |a Wen Lei |e verfasserin |4 aut | |
700 | 0 | |a Wenbin Qian |e verfasserin |4 aut | |
700 | 0 | |a Wenbin Qian |e verfasserin |4 aut | |
700 | 0 | |a Wenbin Qian |e verfasserin |4 aut | |
773 | 0 | 8 | |i In |t Frontiers in Immunology |d Frontiers Media S.A., 2011 |g 11(2020) |w (DE-627)DOAJ000031690 |x 16643224 |7 nnns |
773 | 1 | 8 | |g volume:11 |g year:2020 |
856 | 4 | 0 | |u https://doi.org/10.3389/fimmu.2020.01787 |z kostenfrei |
856 | 4 | 0 | |u https://doaj.org/article/4973f52380d84a0f881b7c8192f60106 |z kostenfrei |
856 | 4 | 0 | |u https://www.frontiersin.org/article/10.3389/fimmu.2020.01787/full |z kostenfrei |
856 | 4 | 2 | |u https://doaj.org/toc/1664-3224 |y Journal toc |z kostenfrei |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_DOAJ | ||
951 | |a AR | ||
952 | |d 11 |j 2020 |