Inhibition of Cholesterol Esterification Enzyme Enhances the Potency of Human Chimeric Antigen Receptor T Cells against Pancreatic Carcinoma

This study aimed to assess the effectiveness of inhibiting cholesterol acyltransferase 1 (ACAT-1) in chimeric antigen receptor T (CAR-T) cells on potentiating the antitumor response against mesothelin (MSLN)-expressing pancreatic carcinoma (PC) cells. We engineered ACAT-1-inhibited CAR-T cells (CAR-...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Lei Zhao [verfasserIn] Yang Liu [verfasserIn] Fuya Zhao [verfasserIn] Ye Jin [verfasserIn] Jing Feng [verfasserIn] Rui Geng [verfasserIn] Jiayu Sun [verfasserIn] Liqing Kang [verfasserIn] Lei Yu [verfasserIn] Yunwei Wei [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Übergeordnetes Werk:	In: Molecular Therapy: Oncolytics - Elsevier, 2016, 16(2020), Seite 262-271
Übergeordnetes Werk:	volume:16 ; year:2020 ; pages:262-271

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1016/j.omto.2020.01.008

Katalog-ID:	DOAJ00988534X

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520			\|a This study aimed to assess the effectiveness of inhibiting cholesterol acyltransferase 1 (ACAT-1) in chimeric antigen receptor T (CAR-T) cells on potentiating the antitumor response against mesothelin (MSLN)-expressing pancreatic carcinoma (PC) cells. We engineered ACAT-1-inhibited CAR-T cells (CAR-T-1847 and CAR-T-1848) using the targeting MSLN CAR lentiviral vector and small interfering RNA (siRNA) targeting the conserved region of the ACAT-1 gene, and characterized the efficacy of these modified CAR-T cells in terms of the cytotoxicity and cytokine release of both MSLN-positive and MSLN-negative PC cells using in vitro methods and in vivo mouse xenografts. The ACAT-1-inhibited CAR-T-1847 and CAR-T-1848 cells showed a higher cytotoxicity at effector-to-target cell (E:T) ratios of 8:1 and 10:1, respectively, and induced a higher secretion of proinflammatory cytokines interleukin-2 (IL-2) and interferon-gamma (IFNγ) in vitro. In addition, bioluminescence imaging of tumor xenografts of ACAT-1-inhibited targeting MSLN CAR-T cells in MSLN-positive PC mice in vivo showed significant tumor regression, which is consistent with the in vitro observations. Our findings demonstrate a novel immunotherapeutic strategy involving the transplantation of ACAT-1-inhibited targeting MSLN CAR-T cells and the feasibility of enhancing the antitumor potency of CAR-T through the novel strategy.
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allfields	10.1016/j.omto.2020.01.008 doi (DE-627)DOAJ00988534X (DE-599)DOAJ5e83bcb3f2d7466e934bde76dbbe0d2b DE-627 ger DE-627 rakwb eng RC254-282 Lei Zhao verfasserin aut Inhibition of Cholesterol Esterification Enzyme Enhances the Potency of Human Chimeric Antigen Receptor T Cells against Pancreatic Carcinoma 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier This study aimed to assess the effectiveness of inhibiting cholesterol acyltransferase 1 (ACAT-1) in chimeric antigen receptor T (CAR-T) cells on potentiating the antitumor response against mesothelin (MSLN)-expressing pancreatic carcinoma (PC) cells. We engineered ACAT-1-inhibited CAR-T cells (CAR-T-1847 and CAR-T-1848) using the targeting MSLN CAR lentiviral vector and small interfering RNA (siRNA) targeting the conserved region of the ACAT-1 gene, and characterized the efficacy of these modified CAR-T cells in terms of the cytotoxicity and cytokine release of both MSLN-positive and MSLN-negative PC cells using in vitro methods and in vivo mouse xenografts. The ACAT-1-inhibited CAR-T-1847 and CAR-T-1848 cells showed a higher cytotoxicity at effector-to-target cell (E:T) ratios of 8:1 and 10:1, respectively, and induced a higher secretion of proinflammatory cytokines interleukin-2 (IL-2) and interferon-gamma (IFNγ) in vitro. In addition, bioluminescence imaging of tumor xenografts of ACAT-1-inhibited targeting MSLN CAR-T cells in MSLN-positive PC mice in vivo showed significant tumor regression, which is consistent with the in vitro observations. Our findings demonstrate a novel immunotherapeutic strategy involving the transplantation of ACAT-1-inhibited targeting MSLN CAR-T cells and the feasibility of enhancing the antitumor potency of CAR-T through the novel strategy. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Yang Liu verfasserin aut Fuya Zhao verfasserin aut Ye Jin verfasserin aut Jing Feng verfasserin aut Rui Geng verfasserin aut Jiayu Sun verfasserin aut Liqing Kang verfasserin aut Lei Yu verfasserin aut Yunwei Wei verfasserin aut In Molecular Therapy: Oncolytics Elsevier, 2016 16(2020), Seite 262-271 (DE-627)843857420 (DE-600)2842549-2 23727705 nnns volume:16 year:2020 pages:262-271 https://doi.org/10.1016/j.omto.2020.01.008 kostenfrei https://doaj.org/article/5e83bcb3f2d7466e934bde76dbbe0d2b kostenfrei http://www.sciencedirect.com/science/article/pii/S2372770520300188 kostenfrei https://doaj.org/toc/2372-7705 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2020 262-271
spelling	10.1016/j.omto.2020.01.008 doi (DE-627)DOAJ00988534X (DE-599)DOAJ5e83bcb3f2d7466e934bde76dbbe0d2b DE-627 ger DE-627 rakwb eng RC254-282 Lei Zhao verfasserin aut Inhibition of Cholesterol Esterification Enzyme Enhances the Potency of Human Chimeric Antigen Receptor T Cells against Pancreatic Carcinoma 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier This study aimed to assess the effectiveness of inhibiting cholesterol acyltransferase 1 (ACAT-1) in chimeric antigen receptor T (CAR-T) cells on potentiating the antitumor response against mesothelin (MSLN)-expressing pancreatic carcinoma (PC) cells. We engineered ACAT-1-inhibited CAR-T cells (CAR-T-1847 and CAR-T-1848) using the targeting MSLN CAR lentiviral vector and small interfering RNA (siRNA) targeting the conserved region of the ACAT-1 gene, and characterized the efficacy of these modified CAR-T cells in terms of the cytotoxicity and cytokine release of both MSLN-positive and MSLN-negative PC cells using in vitro methods and in vivo mouse xenografts. The ACAT-1-inhibited CAR-T-1847 and CAR-T-1848 cells showed a higher cytotoxicity at effector-to-target cell (E:T) ratios of 8:1 and 10:1, respectively, and induced a higher secretion of proinflammatory cytokines interleukin-2 (IL-2) and interferon-gamma (IFNγ) in vitro. In addition, bioluminescence imaging of tumor xenografts of ACAT-1-inhibited targeting MSLN CAR-T cells in MSLN-positive PC mice in vivo showed significant tumor regression, which is consistent with the in vitro observations. Our findings demonstrate a novel immunotherapeutic strategy involving the transplantation of ACAT-1-inhibited targeting MSLN CAR-T cells and the feasibility of enhancing the antitumor potency of CAR-T through the novel strategy. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Yang Liu verfasserin aut Fuya Zhao verfasserin aut Ye Jin verfasserin aut Jing Feng verfasserin aut Rui Geng verfasserin aut Jiayu Sun verfasserin aut Liqing Kang verfasserin aut Lei Yu verfasserin aut Yunwei Wei verfasserin aut In Molecular Therapy: Oncolytics Elsevier, 2016 16(2020), Seite 262-271 (DE-627)843857420 (DE-600)2842549-2 23727705 nnns volume:16 year:2020 pages:262-271 https://doi.org/10.1016/j.omto.2020.01.008 kostenfrei https://doaj.org/article/5e83bcb3f2d7466e934bde76dbbe0d2b kostenfrei http://www.sciencedirect.com/science/article/pii/S2372770520300188 kostenfrei https://doaj.org/toc/2372-7705 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2020 262-271
allfields_unstemmed	10.1016/j.omto.2020.01.008 doi (DE-627)DOAJ00988534X (DE-599)DOAJ5e83bcb3f2d7466e934bde76dbbe0d2b DE-627 ger DE-627 rakwb eng RC254-282 Lei Zhao verfasserin aut Inhibition of Cholesterol Esterification Enzyme Enhances the Potency of Human Chimeric Antigen Receptor T Cells against Pancreatic Carcinoma 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier This study aimed to assess the effectiveness of inhibiting cholesterol acyltransferase 1 (ACAT-1) in chimeric antigen receptor T (CAR-T) cells on potentiating the antitumor response against mesothelin (MSLN)-expressing pancreatic carcinoma (PC) cells. We engineered ACAT-1-inhibited CAR-T cells (CAR-T-1847 and CAR-T-1848) using the targeting MSLN CAR lentiviral vector and small interfering RNA (siRNA) targeting the conserved region of the ACAT-1 gene, and characterized the efficacy of these modified CAR-T cells in terms of the cytotoxicity and cytokine release of both MSLN-positive and MSLN-negative PC cells using in vitro methods and in vivo mouse xenografts. The ACAT-1-inhibited CAR-T-1847 and CAR-T-1848 cells showed a higher cytotoxicity at effector-to-target cell (E:T) ratios of 8:1 and 10:1, respectively, and induced a higher secretion of proinflammatory cytokines interleukin-2 (IL-2) and interferon-gamma (IFNγ) in vitro. In addition, bioluminescence imaging of tumor xenografts of ACAT-1-inhibited targeting MSLN CAR-T cells in MSLN-positive PC mice in vivo showed significant tumor regression, which is consistent with the in vitro observations. Our findings demonstrate a novel immunotherapeutic strategy involving the transplantation of ACAT-1-inhibited targeting MSLN CAR-T cells and the feasibility of enhancing the antitumor potency of CAR-T through the novel strategy. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Yang Liu verfasserin aut Fuya Zhao verfasserin aut Ye Jin verfasserin aut Jing Feng verfasserin aut Rui Geng verfasserin aut Jiayu Sun verfasserin aut Liqing Kang verfasserin aut Lei Yu verfasserin aut Yunwei Wei verfasserin aut In Molecular Therapy: Oncolytics Elsevier, 2016 16(2020), Seite 262-271 (DE-627)843857420 (DE-600)2842549-2 23727705 nnns volume:16 year:2020 pages:262-271 https://doi.org/10.1016/j.omto.2020.01.008 kostenfrei https://doaj.org/article/5e83bcb3f2d7466e934bde76dbbe0d2b kostenfrei http://www.sciencedirect.com/science/article/pii/S2372770520300188 kostenfrei https://doaj.org/toc/2372-7705 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2020 262-271
allfieldsGer	10.1016/j.omto.2020.01.008 doi (DE-627)DOAJ00988534X (DE-599)DOAJ5e83bcb3f2d7466e934bde76dbbe0d2b DE-627 ger DE-627 rakwb eng RC254-282 Lei Zhao verfasserin aut Inhibition of Cholesterol Esterification Enzyme Enhances the Potency of Human Chimeric Antigen Receptor T Cells against Pancreatic Carcinoma 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier This study aimed to assess the effectiveness of inhibiting cholesterol acyltransferase 1 (ACAT-1) in chimeric antigen receptor T (CAR-T) cells on potentiating the antitumor response against mesothelin (MSLN)-expressing pancreatic carcinoma (PC) cells. We engineered ACAT-1-inhibited CAR-T cells (CAR-T-1847 and CAR-T-1848) using the targeting MSLN CAR lentiviral vector and small interfering RNA (siRNA) targeting the conserved region of the ACAT-1 gene, and characterized the efficacy of these modified CAR-T cells in terms of the cytotoxicity and cytokine release of both MSLN-positive and MSLN-negative PC cells using in vitro methods and in vivo mouse xenografts. The ACAT-1-inhibited CAR-T-1847 and CAR-T-1848 cells showed a higher cytotoxicity at effector-to-target cell (E:T) ratios of 8:1 and 10:1, respectively, and induced a higher secretion of proinflammatory cytokines interleukin-2 (IL-2) and interferon-gamma (IFNγ) in vitro. In addition, bioluminescence imaging of tumor xenografts of ACAT-1-inhibited targeting MSLN CAR-T cells in MSLN-positive PC mice in vivo showed significant tumor regression, which is consistent with the in vitro observations. Our findings demonstrate a novel immunotherapeutic strategy involving the transplantation of ACAT-1-inhibited targeting MSLN CAR-T cells and the feasibility of enhancing the antitumor potency of CAR-T through the novel strategy. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Yang Liu verfasserin aut Fuya Zhao verfasserin aut Ye Jin verfasserin aut Jing Feng verfasserin aut Rui Geng verfasserin aut Jiayu Sun verfasserin aut Liqing Kang verfasserin aut Lei Yu verfasserin aut Yunwei Wei verfasserin aut In Molecular Therapy: Oncolytics Elsevier, 2016 16(2020), Seite 262-271 (DE-627)843857420 (DE-600)2842549-2 23727705 nnns volume:16 year:2020 pages:262-271 https://doi.org/10.1016/j.omto.2020.01.008 kostenfrei https://doaj.org/article/5e83bcb3f2d7466e934bde76dbbe0d2b kostenfrei http://www.sciencedirect.com/science/article/pii/S2372770520300188 kostenfrei https://doaj.org/toc/2372-7705 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2020 262-271
allfieldsSound	10.1016/j.omto.2020.01.008 doi (DE-627)DOAJ00988534X (DE-599)DOAJ5e83bcb3f2d7466e934bde76dbbe0d2b DE-627 ger DE-627 rakwb eng RC254-282 Lei Zhao verfasserin aut Inhibition of Cholesterol Esterification Enzyme Enhances the Potency of Human Chimeric Antigen Receptor T Cells against Pancreatic Carcinoma 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier This study aimed to assess the effectiveness of inhibiting cholesterol acyltransferase 1 (ACAT-1) in chimeric antigen receptor T (CAR-T) cells on potentiating the antitumor response against mesothelin (MSLN)-expressing pancreatic carcinoma (PC) cells. We engineered ACAT-1-inhibited CAR-T cells (CAR-T-1847 and CAR-T-1848) using the targeting MSLN CAR lentiviral vector and small interfering RNA (siRNA) targeting the conserved region of the ACAT-1 gene, and characterized the efficacy of these modified CAR-T cells in terms of the cytotoxicity and cytokine release of both MSLN-positive and MSLN-negative PC cells using in vitro methods and in vivo mouse xenografts. The ACAT-1-inhibited CAR-T-1847 and CAR-T-1848 cells showed a higher cytotoxicity at effector-to-target cell (E:T) ratios of 8:1 and 10:1, respectively, and induced a higher secretion of proinflammatory cytokines interleukin-2 (IL-2) and interferon-gamma (IFNγ) in vitro. In addition, bioluminescence imaging of tumor xenografts of ACAT-1-inhibited targeting MSLN CAR-T cells in MSLN-positive PC mice in vivo showed significant tumor regression, which is consistent with the in vitro observations. Our findings demonstrate a novel immunotherapeutic strategy involving the transplantation of ACAT-1-inhibited targeting MSLN CAR-T cells and the feasibility of enhancing the antitumor potency of CAR-T through the novel strategy. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Yang Liu verfasserin aut Fuya Zhao verfasserin aut Ye Jin verfasserin aut Jing Feng verfasserin aut Rui Geng verfasserin aut Jiayu Sun verfasserin aut Liqing Kang verfasserin aut Lei Yu verfasserin aut Yunwei Wei verfasserin aut In Molecular Therapy: Oncolytics Elsevier, 2016 16(2020), Seite 262-271 (DE-627)843857420 (DE-600)2842549-2 23727705 nnns volume:16 year:2020 pages:262-271 https://doi.org/10.1016/j.omto.2020.01.008 kostenfrei https://doaj.org/article/5e83bcb3f2d7466e934bde76dbbe0d2b kostenfrei http://www.sciencedirect.com/science/article/pii/S2372770520300188 kostenfrei https://doaj.org/toc/2372-7705 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2020 262-271
language	English
source	In Molecular Therapy: Oncolytics 16(2020), Seite 262-271 volume:16 year:2020 pages:262-271
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authorswithroles_txt_mv	Lei Zhao @@aut@@ Yang Liu @@aut@@ Fuya Zhao @@aut@@ Ye Jin @@aut@@ Jing Feng @@aut@@ Rui Geng @@aut@@ Jiayu Sun @@aut@@ Liqing Kang @@aut@@ Lei Yu @@aut@@ Yunwei Wei @@aut@@
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callnumber-first	R - Medicine
author	Lei Zhao
spellingShingle	Lei Zhao misc RC254-282 misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens Inhibition of Cholesterol Esterification Enzyme Enhances the Potency of Human Chimeric Antigen Receptor T Cells against Pancreatic Carcinoma
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topic_title	RC254-282 Inhibition of Cholesterol Esterification Enzyme Enhances the Potency of Human Chimeric Antigen Receptor T Cells against Pancreatic Carcinoma
topic	misc RC254-282 misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_unstemmed	misc RC254-282 misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_browse	misc RC254-282 misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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title	Inhibition of Cholesterol Esterification Enzyme Enhances the Potency of Human Chimeric Antigen Receptor T Cells against Pancreatic Carcinoma
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title_full	Inhibition of Cholesterol Esterification Enzyme Enhances the Potency of Human Chimeric Antigen Receptor T Cells against Pancreatic Carcinoma
author_sort	Lei Zhao
journal	Molecular Therapy: Oncolytics
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author_browse	Lei Zhao Yang Liu Fuya Zhao Ye Jin Jing Feng Rui Geng Jiayu Sun Liqing Kang Lei Yu Yunwei Wei
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doi_str_mv	10.1016/j.omto.2020.01.008
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title_sort	inhibition of cholesterol esterification enzyme enhances the potency of human chimeric antigen receptor t cells against pancreatic carcinoma
callnumber	RC254-282
title_auth	Inhibition of Cholesterol Esterification Enzyme Enhances the Potency of Human Chimeric Antigen Receptor T Cells against Pancreatic Carcinoma
abstract	This study aimed to assess the effectiveness of inhibiting cholesterol acyltransferase 1 (ACAT-1) in chimeric antigen receptor T (CAR-T) cells on potentiating the antitumor response against mesothelin (MSLN)-expressing pancreatic carcinoma (PC) cells. We engineered ACAT-1-inhibited CAR-T cells (CAR-T-1847 and CAR-T-1848) using the targeting MSLN CAR lentiviral vector and small interfering RNA (siRNA) targeting the conserved region of the ACAT-1 gene, and characterized the efficacy of these modified CAR-T cells in terms of the cytotoxicity and cytokine release of both MSLN-positive and MSLN-negative PC cells using in vitro methods and in vivo mouse xenografts. The ACAT-1-inhibited CAR-T-1847 and CAR-T-1848 cells showed a higher cytotoxicity at effector-to-target cell (E:T) ratios of 8:1 and 10:1, respectively, and induced a higher secretion of proinflammatory cytokines interleukin-2 (IL-2) and interferon-gamma (IFNγ) in vitro. In addition, bioluminescence imaging of tumor xenografts of ACAT-1-inhibited targeting MSLN CAR-T cells in MSLN-positive PC mice in vivo showed significant tumor regression, which is consistent with the in vitro observations. Our findings demonstrate a novel immunotherapeutic strategy involving the transplantation of ACAT-1-inhibited targeting MSLN CAR-T cells and the feasibility of enhancing the antitumor potency of CAR-T through the novel strategy.
abstractGer	This study aimed to assess the effectiveness of inhibiting cholesterol acyltransferase 1 (ACAT-1) in chimeric antigen receptor T (CAR-T) cells on potentiating the antitumor response against mesothelin (MSLN)-expressing pancreatic carcinoma (PC) cells. We engineered ACAT-1-inhibited CAR-T cells (CAR-T-1847 and CAR-T-1848) using the targeting MSLN CAR lentiviral vector and small interfering RNA (siRNA) targeting the conserved region of the ACAT-1 gene, and characterized the efficacy of these modified CAR-T cells in terms of the cytotoxicity and cytokine release of both MSLN-positive and MSLN-negative PC cells using in vitro methods and in vivo mouse xenografts. The ACAT-1-inhibited CAR-T-1847 and CAR-T-1848 cells showed a higher cytotoxicity at effector-to-target cell (E:T) ratios of 8:1 and 10:1, respectively, and induced a higher secretion of proinflammatory cytokines interleukin-2 (IL-2) and interferon-gamma (IFNγ) in vitro. In addition, bioluminescence imaging of tumor xenografts of ACAT-1-inhibited targeting MSLN CAR-T cells in MSLN-positive PC mice in vivo showed significant tumor regression, which is consistent with the in vitro observations. Our findings demonstrate a novel immunotherapeutic strategy involving the transplantation of ACAT-1-inhibited targeting MSLN CAR-T cells and the feasibility of enhancing the antitumor potency of CAR-T through the novel strategy.
abstract_unstemmed	This study aimed to assess the effectiveness of inhibiting cholesterol acyltransferase 1 (ACAT-1) in chimeric antigen receptor T (CAR-T) cells on potentiating the antitumor response against mesothelin (MSLN)-expressing pancreatic carcinoma (PC) cells. We engineered ACAT-1-inhibited CAR-T cells (CAR-T-1847 and CAR-T-1848) using the targeting MSLN CAR lentiviral vector and small interfering RNA (siRNA) targeting the conserved region of the ACAT-1 gene, and characterized the efficacy of these modified CAR-T cells in terms of the cytotoxicity and cytokine release of both MSLN-positive and MSLN-negative PC cells using in vitro methods and in vivo mouse xenografts. The ACAT-1-inhibited CAR-T-1847 and CAR-T-1848 cells showed a higher cytotoxicity at effector-to-target cell (E:T) ratios of 8:1 and 10:1, respectively, and induced a higher secretion of proinflammatory cytokines interleukin-2 (IL-2) and interferon-gamma (IFNγ) in vitro. In addition, bioluminescence imaging of tumor xenografts of ACAT-1-inhibited targeting MSLN CAR-T cells in MSLN-positive PC mice in vivo showed significant tumor regression, which is consistent with the in vitro observations. Our findings demonstrate a novel immunotherapeutic strategy involving the transplantation of ACAT-1-inhibited targeting MSLN CAR-T cells and the feasibility of enhancing the antitumor potency of CAR-T through the novel strategy.
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title_short	Inhibition of Cholesterol Esterification Enzyme Enhances the Potency of Human Chimeric Antigen Receptor T Cells against Pancreatic Carcinoma
url	https://doi.org/10.1016/j.omto.2020.01.008 https://doaj.org/article/5e83bcb3f2d7466e934bde76dbbe0d2b http://www.sciencedirect.com/science/article/pii/S2372770520300188 https://doaj.org/toc/2372-7705
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author2	Yang Liu Fuya Zhao Ye Jin Jing Feng Rui Geng Jiayu Sun Liqing Kang Lei Yu Yunwei Wei
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up_date	2024-07-04T01:25:49.904Z
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