Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer

Background Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.Methods The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.Results Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.Conclusions Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Su Jeong Song [verfasserIn] Seohyun Kim [verfasserIn] Seong A Kim [verfasserIn] Gi-Hoon Nam [verfasserIn] Gi Beom Kim [verfasserIn] Yoonjeong Choi [verfasserIn] Minsu Kwon [verfasserIn] Cherlhyun Jeong [verfasserIn] Hanul Jung [verfasserIn] Eunbyeol Ko [verfasserIn] Yeji Lee [verfasserIn] Jihoon Han [verfasserIn] Jiwan Woo [verfasserIn] Yakdol Cho [verfasserIn] Seung-Yoon Park [verfasserIn] Thomas M. Roberts [verfasserIn] Yong Beom Cho [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Übergeordnetes Werk:	In: Journal for ImmunoTherapy of Cancer - BMJ Publishing Group, 2013, 9(2021), 7
Übergeordnetes Werk:	volume:9 ; year:2021 ; number:7

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1136/jitc-2021-002474

Katalog-ID:	DOAJ006197248

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520			\|a Background Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.Methods The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.Results Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.Conclusions Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity.
653		0	\|a Neoplasms. Tumors. Oncology. Including cancer and carcinogens
700	0		\|a Seohyun Kim \|e verfasserin \|4 aut
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700	0		\|a Gi-Hoon Nam \|e verfasserin \|4 aut
700	0		\|a Gi Beom Kim \|e verfasserin \|4 aut
700	0		\|a Yoonjeong Choi \|e verfasserin \|4 aut
700	0		\|a Minsu Kwon \|e verfasserin \|4 aut
700	0		\|a Cherlhyun Jeong \|e verfasserin \|4 aut
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700	0		\|a Seung-Yoon Park \|e verfasserin \|4 aut
700	0		\|a Thomas M. Roberts \|e verfasserin \|4 aut
700	0		\|a Yong Beom Cho \|e verfasserin \|4 aut
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allfields	10.1136/jitc-2021-002474 doi (DE-627)DOAJ006197248 (DE-599)DOAJ7aae6edcd1d94399a85da57101e56e96 DE-627 ger DE-627 rakwb eng RC254-282 Su Jeong Song verfasserin aut Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.Methods The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.Results Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.Conclusions Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Seohyun Kim verfasserin aut Seong A Kim verfasserin aut Gi-Hoon Nam verfasserin aut Gi Beom Kim verfasserin aut Yoonjeong Choi verfasserin aut Minsu Kwon verfasserin aut Cherlhyun Jeong verfasserin aut Hanul Jung verfasserin aut Eunbyeol Ko verfasserin aut Yeji Lee verfasserin aut Jihoon Han verfasserin aut Jiwan Woo verfasserin aut Yakdol Cho verfasserin aut Seung-Yoon Park verfasserin aut Thomas M. Roberts verfasserin aut Yong Beom Cho verfasserin aut In Journal for ImmunoTherapy of Cancer BMJ Publishing Group, 2013 9(2021), 7 (DE-627)750086335 (DE-600)2719863-7 20511426 nnns volume:9 year:2021 number:7 https://doi.org/10.1136/jitc-2021-002474 kostenfrei https://doaj.org/article/7aae6edcd1d94399a85da57101e56e96 kostenfrei https://jitc.bmj.com/content/9/7/e002474.full kostenfrei https://doaj.org/toc/2051-1426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 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_2003 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 9 2021 7
spelling	10.1136/jitc-2021-002474 doi (DE-627)DOAJ006197248 (DE-599)DOAJ7aae6edcd1d94399a85da57101e56e96 DE-627 ger DE-627 rakwb eng RC254-282 Su Jeong Song verfasserin aut Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.Methods The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.Results Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.Conclusions Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Seohyun Kim verfasserin aut Seong A Kim verfasserin aut Gi-Hoon Nam verfasserin aut Gi Beom Kim verfasserin aut Yoonjeong Choi verfasserin aut Minsu Kwon verfasserin aut Cherlhyun Jeong verfasserin aut Hanul Jung verfasserin aut Eunbyeol Ko verfasserin aut Yeji Lee verfasserin aut Jihoon Han verfasserin aut Jiwan Woo verfasserin aut Yakdol Cho verfasserin aut Seung-Yoon Park verfasserin aut Thomas M. Roberts verfasserin aut Yong Beom Cho verfasserin aut In Journal for ImmunoTherapy of Cancer BMJ Publishing Group, 2013 9(2021), 7 (DE-627)750086335 (DE-600)2719863-7 20511426 nnns volume:9 year:2021 number:7 https://doi.org/10.1136/jitc-2021-002474 kostenfrei https://doaj.org/article/7aae6edcd1d94399a85da57101e56e96 kostenfrei https://jitc.bmj.com/content/9/7/e002474.full kostenfrei https://doaj.org/toc/2051-1426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 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_2003 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 9 2021 7
allfields_unstemmed	10.1136/jitc-2021-002474 doi (DE-627)DOAJ006197248 (DE-599)DOAJ7aae6edcd1d94399a85da57101e56e96 DE-627 ger DE-627 rakwb eng RC254-282 Su Jeong Song verfasserin aut Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.Methods The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.Results Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.Conclusions Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Seohyun Kim verfasserin aut Seong A Kim verfasserin aut Gi-Hoon Nam verfasserin aut Gi Beom Kim verfasserin aut Yoonjeong Choi verfasserin aut Minsu Kwon verfasserin aut Cherlhyun Jeong verfasserin aut Hanul Jung verfasserin aut Eunbyeol Ko verfasserin aut Yeji Lee verfasserin aut Jihoon Han verfasserin aut Jiwan Woo verfasserin aut Yakdol Cho verfasserin aut Seung-Yoon Park verfasserin aut Thomas M. Roberts verfasserin aut Yong Beom Cho verfasserin aut In Journal for ImmunoTherapy of Cancer BMJ Publishing Group, 2013 9(2021), 7 (DE-627)750086335 (DE-600)2719863-7 20511426 nnns volume:9 year:2021 number:7 https://doi.org/10.1136/jitc-2021-002474 kostenfrei https://doaj.org/article/7aae6edcd1d94399a85da57101e56e96 kostenfrei https://jitc.bmj.com/content/9/7/e002474.full kostenfrei https://doaj.org/toc/2051-1426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 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_2003 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 9 2021 7
allfieldsGer	10.1136/jitc-2021-002474 doi (DE-627)DOAJ006197248 (DE-599)DOAJ7aae6edcd1d94399a85da57101e56e96 DE-627 ger DE-627 rakwb eng RC254-282 Su Jeong Song verfasserin aut Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.Methods The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.Results Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.Conclusions Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Seohyun Kim verfasserin aut Seong A Kim verfasserin aut Gi-Hoon Nam verfasserin aut Gi Beom Kim verfasserin aut Yoonjeong Choi verfasserin aut Minsu Kwon verfasserin aut Cherlhyun Jeong verfasserin aut Hanul Jung verfasserin aut Eunbyeol Ko verfasserin aut Yeji Lee verfasserin aut Jihoon Han verfasserin aut Jiwan Woo verfasserin aut Yakdol Cho verfasserin aut Seung-Yoon Park verfasserin aut Thomas M. Roberts verfasserin aut Yong Beom Cho verfasserin aut In Journal for ImmunoTherapy of Cancer BMJ Publishing Group, 2013 9(2021), 7 (DE-627)750086335 (DE-600)2719863-7 20511426 nnns volume:9 year:2021 number:7 https://doi.org/10.1136/jitc-2021-002474 kostenfrei https://doaj.org/article/7aae6edcd1d94399a85da57101e56e96 kostenfrei https://jitc.bmj.com/content/9/7/e002474.full kostenfrei https://doaj.org/toc/2051-1426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 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_2003 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 9 2021 7
allfieldsSound	10.1136/jitc-2021-002474 doi (DE-627)DOAJ006197248 (DE-599)DOAJ7aae6edcd1d94399a85da57101e56e96 DE-627 ger DE-627 rakwb eng RC254-282 Su Jeong Song verfasserin aut Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.Methods The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.Results Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.Conclusions Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity. Neoplasms. Tumors. Oncology. Including cancer and carcinogens Seohyun Kim verfasserin aut Seong A Kim verfasserin aut Gi-Hoon Nam verfasserin aut Gi Beom Kim verfasserin aut Yoonjeong Choi verfasserin aut Minsu Kwon verfasserin aut Cherlhyun Jeong verfasserin aut Hanul Jung verfasserin aut Eunbyeol Ko verfasserin aut Yeji Lee verfasserin aut Jihoon Han verfasserin aut Jiwan Woo verfasserin aut Yakdol Cho verfasserin aut Seung-Yoon Park verfasserin aut Thomas M. Roberts verfasserin aut Yong Beom Cho verfasserin aut In Journal for ImmunoTherapy of Cancer BMJ Publishing Group, 2013 9(2021), 7 (DE-627)750086335 (DE-600)2719863-7 20511426 nnns volume:9 year:2021 number:7 https://doi.org/10.1136/jitc-2021-002474 kostenfrei https://doaj.org/article/7aae6edcd1d94399a85da57101e56e96 kostenfrei https://jitc.bmj.com/content/9/7/e002474.full kostenfrei https://doaj.org/toc/2051-1426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 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_2003 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 9 2021 7
language	English
source	In Journal for ImmunoTherapy of Cancer 9(2021), 7 volume:9 year:2021 number:7
sourceStr	In Journal for ImmunoTherapy of Cancer 9(2021), 7 volume:9 year:2021 number:7
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Neoplasms. Tumors. Oncology. Including cancer and carcinogens
isfreeaccess_bool	true
container_title	Journal for ImmunoTherapy of Cancer
authorswithroles_txt_mv	Su Jeong Song @@aut@@ Seohyun Kim @@aut@@ Seong A Kim @@aut@@ Gi-Hoon Nam @@aut@@ Gi Beom Kim @@aut@@ Yoonjeong Choi @@aut@@ Minsu Kwon @@aut@@ Cherlhyun Jeong @@aut@@ Hanul Jung @@aut@@ Eunbyeol Ko @@aut@@ Yeji Lee @@aut@@ Jihoon Han @@aut@@ Jiwan Woo @@aut@@ Yakdol Cho @@aut@@ Seung-Yoon Park @@aut@@ Thomas M. Roberts @@aut@@ Yong Beom Cho @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	750086335
id	DOAJ006197248
language_de	englisch
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However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.Methods The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.Results Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.Conclusions Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity.</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Neoplasms. Tumors. Oncology. 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callnumber-first	R - Medicine
author	Su Jeong Song
spellingShingle	Su Jeong Song misc RC254-282 misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer
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topic_title	RC254-282 Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer
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
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title	Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer
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title_full	Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer
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author_browse	Su Jeong Song Seohyun Kim Seong A Kim Gi-Hoon Nam Gi Beom Kim Yoonjeong Choi Minsu Kwon Cherlhyun Jeong Hanul Jung Eunbyeol Ko Yeji Lee Jihoon Han Jiwan Woo Yakdol Cho Seung-Yoon Park Thomas M. Roberts Yong Beom Cho
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title_sort	statin-mediated inhibition of ras prenylation activates er stress to enhance the immunogenicity of kras mutant cancer
callnumber	RC254-282
title_auth	Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer
abstract	Background Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.Methods The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.Results Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.Conclusions Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity.
abstractGer	Background Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.Methods The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.Results Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.Conclusions Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity.
abstract_unstemmed	Background Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.Methods The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.Results Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.Conclusions Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity.
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title_short	Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer
url	https://doi.org/10.1136/jitc-2021-002474 https://doaj.org/article/7aae6edcd1d94399a85da57101e56e96 https://jitc.bmj.com/content/9/7/e002474.full https://doaj.org/toc/2051-1426
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up_date	2024-07-03T19:32:38.914Z
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Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer

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