Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity

Abstract Immunotherapy has transformed cancer treatments; however, a large fraction of patients encounter resistance. Such resistance is mediated by complex factors, often involving interactions between multiple genes. Thus, it is crucially important to identify genetic interactions between genes th...
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Gespeichert in:

Autor*in:	Jonathan J. Park [verfasserIn] Adan Codina [verfasserIn] Lupeng Ye [verfasserIn] Stanley Lam [verfasserIn] Jianjian Guo [verfasserIn] Paul Clark [verfasserIn] Xiaoyu Zhou [verfasserIn] Lei Peng [verfasserIn] Sidi Chen [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	CRISPR screen Immunotherapy Cancer immunology Genetic interaction Double knockout Systems biology

Übergeordnetes Werk:	In: Journal of Hematology & Oncology - BMC, 2008, 15(2022), 1, Seite 5
Übergeordnetes Werk:	volume:15 ; year:2022 ; number:1 ; pages:5

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/s13045-022-01389-y

Katalog-ID:	DOAJ026446081

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520			\|a Abstract Immunotherapy has transformed cancer treatments; however, a large fraction of patients encounter resistance. Such resistance is mediated by complex factors, often involving interactions between multiple genes. Thus, it is crucially important to identify genetic interactions between genes that are significantly mutated in cancer patients and those involved in immune responses, ideally the ones that currently have chemical compounds for direct targeting. To systematically interrogate such genetic interactions that mediate cancer cells’ response to T cell killing, we designed an asymmetric dual perturbation library targeting the matched combinations between significantly mutated tumor suppressors and immune resistance genes. We performed a combinatorial double knockout screen on 1159 gene pairs and identified those where joint loss-of-function renders altered cellular response to T cell cytotoxicity. We also performed comparative transcriptomics-based analyses on tumor and normal samples from TCGA and GTEx cohorts, mutational profiling analyses, and survival analyses to further characterize the significance of identified hits in clinical patients. Interactions between significantly mutated tumor suppressors and potentially druggable immune resistance genes may offer insights on potential new concepts of how to target clinically relevant cancer mutations with currently available agents. This study also provides a technology platform and an asymmetric double knockout library for interrogating genetic interactions between cancer mutations and immune resistance pathways under various settings.
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650		4	\|a Double knockout
650		4	\|a Systems biology
653		0	\|a Diseases of the blood and blood-forming organs
653		0	\|a Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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allfields	10.1186/s13045-022-01389-y doi (DE-627)DOAJ026446081 (DE-599)DOAJ157727462f2c47acbcd85d3775f2ea63 DE-627 ger DE-627 rakwb eng RC633-647.5 RC254-282 Jonathan J. Park verfasserin aut Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Immunotherapy has transformed cancer treatments; however, a large fraction of patients encounter resistance. Such resistance is mediated by complex factors, often involving interactions between multiple genes. Thus, it is crucially important to identify genetic interactions between genes that are significantly mutated in cancer patients and those involved in immune responses, ideally the ones that currently have chemical compounds for direct targeting. To systematically interrogate such genetic interactions that mediate cancer cells’ response to T cell killing, we designed an asymmetric dual perturbation library targeting the matched combinations between significantly mutated tumor suppressors and immune resistance genes. We performed a combinatorial double knockout screen on 1159 gene pairs and identified those where joint loss-of-function renders altered cellular response to T cell cytotoxicity. We also performed comparative transcriptomics-based analyses on tumor and normal samples from TCGA and GTEx cohorts, mutational profiling analyses, and survival analyses to further characterize the significance of identified hits in clinical patients. Interactions between significantly mutated tumor suppressors and potentially druggable immune resistance genes may offer insights on potential new concepts of how to target clinically relevant cancer mutations with currently available agents. This study also provides a technology platform and an asymmetric double knockout library for interrogating genetic interactions between cancer mutations and immune resistance pathways under various settings. CRISPR screen Immunotherapy Cancer immunology Genetic interaction Double knockout Systems biology Diseases of the blood and blood-forming organs Neoplasms. Tumors. Oncology. Including cancer and carcinogens Adan Codina verfasserin aut Lupeng Ye verfasserin aut Stanley Lam verfasserin aut Jianjian Guo verfasserin aut Paul Clark verfasserin aut Xiaoyu Zhou verfasserin aut Lei Peng verfasserin aut Sidi Chen verfasserin aut In Journal of Hematology & Oncology BMC, 2008 15(2022), 1, Seite 5 (DE-627)568914813 (DE-600)2429631-4 17568722 nnns volume:15 year:2022 number:1 pages:5 https://doi.org/10.1186/s13045-022-01389-y kostenfrei https://doaj.org/article/157727462f2c47acbcd85d3775f2ea63 kostenfrei https://doi.org/10.1186/s13045-022-01389-y kostenfrei https://doaj.org/toc/1756-8722 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 15 2022 1 5
spelling	10.1186/s13045-022-01389-y doi (DE-627)DOAJ026446081 (DE-599)DOAJ157727462f2c47acbcd85d3775f2ea63 DE-627 ger DE-627 rakwb eng RC633-647.5 RC254-282 Jonathan J. Park verfasserin aut Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Immunotherapy has transformed cancer treatments; however, a large fraction of patients encounter resistance. Such resistance is mediated by complex factors, often involving interactions between multiple genes. Thus, it is crucially important to identify genetic interactions between genes that are significantly mutated in cancer patients and those involved in immune responses, ideally the ones that currently have chemical compounds for direct targeting. To systematically interrogate such genetic interactions that mediate cancer cells’ response to T cell killing, we designed an asymmetric dual perturbation library targeting the matched combinations between significantly mutated tumor suppressors and immune resistance genes. We performed a combinatorial double knockout screen on 1159 gene pairs and identified those where joint loss-of-function renders altered cellular response to T cell cytotoxicity. We also performed comparative transcriptomics-based analyses on tumor and normal samples from TCGA and GTEx cohorts, mutational profiling analyses, and survival analyses to further characterize the significance of identified hits in clinical patients. Interactions between significantly mutated tumor suppressors and potentially druggable immune resistance genes may offer insights on potential new concepts of how to target clinically relevant cancer mutations with currently available agents. This study also provides a technology platform and an asymmetric double knockout library for interrogating genetic interactions between cancer mutations and immune resistance pathways under various settings. CRISPR screen Immunotherapy Cancer immunology Genetic interaction Double knockout Systems biology Diseases of the blood and blood-forming organs Neoplasms. Tumors. Oncology. Including cancer and carcinogens Adan Codina verfasserin aut Lupeng Ye verfasserin aut Stanley Lam verfasserin aut Jianjian Guo verfasserin aut Paul Clark verfasserin aut Xiaoyu Zhou verfasserin aut Lei Peng verfasserin aut Sidi Chen verfasserin aut In Journal of Hematology & Oncology BMC, 2008 15(2022), 1, Seite 5 (DE-627)568914813 (DE-600)2429631-4 17568722 nnns volume:15 year:2022 number:1 pages:5 https://doi.org/10.1186/s13045-022-01389-y kostenfrei https://doaj.org/article/157727462f2c47acbcd85d3775f2ea63 kostenfrei https://doi.org/10.1186/s13045-022-01389-y kostenfrei https://doaj.org/toc/1756-8722 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 15 2022 1 5
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allfieldsSound	10.1186/s13045-022-01389-y doi (DE-627)DOAJ026446081 (DE-599)DOAJ157727462f2c47acbcd85d3775f2ea63 DE-627 ger DE-627 rakwb eng RC633-647.5 RC254-282 Jonathan J. Park verfasserin aut Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Immunotherapy has transformed cancer treatments; however, a large fraction of patients encounter resistance. Such resistance is mediated by complex factors, often involving interactions between multiple genes. Thus, it is crucially important to identify genetic interactions between genes that are significantly mutated in cancer patients and those involved in immune responses, ideally the ones that currently have chemical compounds for direct targeting. To systematically interrogate such genetic interactions that mediate cancer cells’ response to T cell killing, we designed an asymmetric dual perturbation library targeting the matched combinations between significantly mutated tumor suppressors and immune resistance genes. We performed a combinatorial double knockout screen on 1159 gene pairs and identified those where joint loss-of-function renders altered cellular response to T cell cytotoxicity. We also performed comparative transcriptomics-based analyses on tumor and normal samples from TCGA and GTEx cohorts, mutational profiling analyses, and survival analyses to further characterize the significance of identified hits in clinical patients. Interactions between significantly mutated tumor suppressors and potentially druggable immune resistance genes may offer insights on potential new concepts of how to target clinically relevant cancer mutations with currently available agents. This study also provides a technology platform and an asymmetric double knockout library for interrogating genetic interactions between cancer mutations and immune resistance pathways under various settings. CRISPR screen Immunotherapy Cancer immunology Genetic interaction Double knockout Systems biology Diseases of the blood and blood-forming organs Neoplasms. Tumors. Oncology. Including cancer and carcinogens Adan Codina verfasserin aut Lupeng Ye verfasserin aut Stanley Lam verfasserin aut Jianjian Guo verfasserin aut Paul Clark verfasserin aut Xiaoyu Zhou verfasserin aut Lei Peng verfasserin aut Sidi Chen verfasserin aut In Journal of Hematology & Oncology BMC, 2008 15(2022), 1, Seite 5 (DE-627)568914813 (DE-600)2429631-4 17568722 nnns volume:15 year:2022 number:1 pages:5 https://doi.org/10.1186/s13045-022-01389-y kostenfrei https://doaj.org/article/157727462f2c47acbcd85d3775f2ea63 kostenfrei https://doi.org/10.1186/s13045-022-01389-y kostenfrei https://doaj.org/toc/1756-8722 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 15 2022 1 5
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Park</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2022</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Immunotherapy has transformed cancer treatments; however, a large fraction of patients encounter resistance. 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callnumber-first	R - Medicine
author	Jonathan J. Park
spellingShingle	Jonathan J. Park misc RC633-647.5 misc RC254-282 misc CRISPR screen misc Immunotherapy misc Cancer immunology misc Genetic interaction misc Double knockout misc Systems biology misc Diseases of the blood and blood-forming organs misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity
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topic_title	RC633-647.5 RC254-282 Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity CRISPR screen Immunotherapy Cancer immunology Genetic interaction Double knockout Systems biology
topic	misc RC633-647.5 misc RC254-282 misc CRISPR screen misc Immunotherapy misc Cancer immunology misc Genetic interaction misc Double knockout misc Systems biology misc Diseases of the blood and blood-forming organs misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_unstemmed	misc RC633-647.5 misc RC254-282 misc CRISPR screen misc Immunotherapy misc Cancer immunology misc Genetic interaction misc Double knockout misc Systems biology misc Diseases of the blood and blood-forming organs misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_browse	misc RC633-647.5 misc RC254-282 misc CRISPR screen misc Immunotherapy misc Cancer immunology misc Genetic interaction misc Double knockout misc Systems biology misc Diseases of the blood and blood-forming organs misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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title	Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity
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title_full	Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity
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title_sort	double knockout crispr screen for cancer resistance to t cell cytotoxicity
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title_auth	Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity
abstract	Abstract Immunotherapy has transformed cancer treatments; however, a large fraction of patients encounter resistance. Such resistance is mediated by complex factors, often involving interactions between multiple genes. Thus, it is crucially important to identify genetic interactions between genes that are significantly mutated in cancer patients and those involved in immune responses, ideally the ones that currently have chemical compounds for direct targeting. To systematically interrogate such genetic interactions that mediate cancer cells’ response to T cell killing, we designed an asymmetric dual perturbation library targeting the matched combinations between significantly mutated tumor suppressors and immune resistance genes. We performed a combinatorial double knockout screen on 1159 gene pairs and identified those where joint loss-of-function renders altered cellular response to T cell cytotoxicity. We also performed comparative transcriptomics-based analyses on tumor and normal samples from TCGA and GTEx cohorts, mutational profiling analyses, and survival analyses to further characterize the significance of identified hits in clinical patients. Interactions between significantly mutated tumor suppressors and potentially druggable immune resistance genes may offer insights on potential new concepts of how to target clinically relevant cancer mutations with currently available agents. This study also provides a technology platform and an asymmetric double knockout library for interrogating genetic interactions between cancer mutations and immune resistance pathways under various settings.
abstractGer	Abstract Immunotherapy has transformed cancer treatments; however, a large fraction of patients encounter resistance. Such resistance is mediated by complex factors, often involving interactions between multiple genes. Thus, it is crucially important to identify genetic interactions between genes that are significantly mutated in cancer patients and those involved in immune responses, ideally the ones that currently have chemical compounds for direct targeting. To systematically interrogate such genetic interactions that mediate cancer cells’ response to T cell killing, we designed an asymmetric dual perturbation library targeting the matched combinations between significantly mutated tumor suppressors and immune resistance genes. We performed a combinatorial double knockout screen on 1159 gene pairs and identified those where joint loss-of-function renders altered cellular response to T cell cytotoxicity. We also performed comparative transcriptomics-based analyses on tumor and normal samples from TCGA and GTEx cohorts, mutational profiling analyses, and survival analyses to further characterize the significance of identified hits in clinical patients. Interactions between significantly mutated tumor suppressors and potentially druggable immune resistance genes may offer insights on potential new concepts of how to target clinically relevant cancer mutations with currently available agents. This study also provides a technology platform and an asymmetric double knockout library for interrogating genetic interactions between cancer mutations and immune resistance pathways under various settings.
abstract_unstemmed	Abstract Immunotherapy has transformed cancer treatments; however, a large fraction of patients encounter resistance. Such resistance is mediated by complex factors, often involving interactions between multiple genes. Thus, it is crucially important to identify genetic interactions between genes that are significantly mutated in cancer patients and those involved in immune responses, ideally the ones that currently have chemical compounds for direct targeting. To systematically interrogate such genetic interactions that mediate cancer cells’ response to T cell killing, we designed an asymmetric dual perturbation library targeting the matched combinations between significantly mutated tumor suppressors and immune resistance genes. We performed a combinatorial double knockout screen on 1159 gene pairs and identified those where joint loss-of-function renders altered cellular response to T cell cytotoxicity. We also performed comparative transcriptomics-based analyses on tumor and normal samples from TCGA and GTEx cohorts, mutational profiling analyses, and survival analyses to further characterize the significance of identified hits in clinical patients. Interactions between significantly mutated tumor suppressors and potentially druggable immune resistance genes may offer insights on potential new concepts of how to target clinically relevant cancer mutations with currently available agents. This study also provides a technology platform and an asymmetric double knockout library for interrogating genetic interactions between cancer mutations and immune resistance pathways under various settings.
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title_short	Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity
url	https://doi.org/10.1186/s13045-022-01389-y https://doaj.org/article/157727462f2c47acbcd85d3775f2ea63 https://doaj.org/toc/1756-8722
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up_date	2024-07-03T21:02:20.794Z
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Park</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2022</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Immunotherapy has transformed cancer treatments; however, a large fraction of patients encounter resistance. 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Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity

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