Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation

Background Chimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part to immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of lactate inducing the formation of immunosuppressive microenvironme...
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Autor*in:	Sun, Ting [verfasserIn] Liu, Bin Li, Yanyan Wu, Jie Cao, Yufei Yang, Shuangyu Tan, Huiling Cai, Lize Zhang, Shiqi Qi, Xinyue Yu, Dingjia Yang, Wei

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	CAR-T Glioblastoma Histone lactylation Ectonucleotidases CCR8

Anmerkung:	© The Author(s) 2023

Übergeordnetes Werk:	Enthalten in: Journal of experimental & clinical cancer research - Berlin : Springer, 2008, 42(2023), 1 vom: 29. Sept.
Übergeordnetes Werk:	volume:42 ; year:2023 ; number:1 ; day:29 ; month:09

Links:	Volltext

DOI / URN:	10.1186/s13046-023-02815-w

Katalog-ID:	SPR053239547

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520			\|a Background Chimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part to immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of lactate inducing the formation of immunosuppressive microenvironment remains to be further explored. Methods Immunocyte subpopulations and molecular characteristics were analyzed in the orthotopic xenografts of nude mice using flow cytometry assay and immunohistochemical staining after oxamate, a lactate dehydrogenase A (LDHA) inhibitor, and control T or CAR-T cells injection alone or in combination. RT-qPCR, western blot, flow cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation and ELISA were performed to measure the effect of lactate on the regulation of CD39, CD73 and CCR8 in cultured glioma stem cells, CD4 + T cells or macrophages. Results Oxamate promoted immune activation of tumor-infiltrating CAR-T cells through altering the phenotypes of immune molecules and increasing regulatory T (Treg) cells infiltration in a glioblastoma mouse model. Lactate accumulation within cells upregulated CD39, CD73 and CCR8 expressions in both lactate-treated cells and glioma stem cells-co-cultured CD4 + T cells and macrophages, and intracellular lactate directly elevated the activities of these gene promotors through histone H3K18 lactylation. Conclusions Utilizing lactate generation inhibitor not only reprogramed glucose metabolism of cancer stem cells, but also alleviated immunosuppression of tumor microenvironment and reduced tumor-infiltrating CAR-Treg cells, which may be a potential strategy to enhance CAR-T function in glioblastoma therapy.
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allfields	10.1186/s13046-023-02815-w doi (DE-627)SPR053239547 (SPR)s13046-023-02815-w-e DE-627 ger DE-627 rakwb eng Sun, Ting verfasserin aut Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Chimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part to immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of lactate inducing the formation of immunosuppressive microenvironment remains to be further explored. Methods Immunocyte subpopulations and molecular characteristics were analyzed in the orthotopic xenografts of nude mice using flow cytometry assay and immunohistochemical staining after oxamate, a lactate dehydrogenase A (LDHA) inhibitor, and control T or CAR-T cells injection alone or in combination. RT-qPCR, western blot, flow cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation and ELISA were performed to measure the effect of lactate on the regulation of CD39, CD73 and CCR8 in cultured glioma stem cells, CD4 + T cells or macrophages. Results Oxamate promoted immune activation of tumor-infiltrating CAR-T cells through altering the phenotypes of immune molecules and increasing regulatory T (Treg) cells infiltration in a glioblastoma mouse model. Lactate accumulation within cells upregulated CD39, CD73 and CCR8 expressions in both lactate-treated cells and glioma stem cells-co-cultured CD4 + T cells and macrophages, and intracellular lactate directly elevated the activities of these gene promotors through histone H3K18 lactylation. Conclusions Utilizing lactate generation inhibitor not only reprogramed glucose metabolism of cancer stem cells, but also alleviated immunosuppression of tumor microenvironment and reduced tumor-infiltrating CAR-Treg cells, which may be a potential strategy to enhance CAR-T function in glioblastoma therapy. CAR-T (dpeaa)DE-He213 Glioblastoma (dpeaa)DE-He213 Histone lactylation (dpeaa)DE-He213 Ectonucleotidases (dpeaa)DE-He213 CCR8 (dpeaa)DE-He213 Liu, Bin aut Li, Yanyan aut Wu, Jie aut Cao, Yufei aut Yang, Shuangyu aut Tan, Huiling aut Cai, Lize aut Zhang, Shiqi aut Qi, Xinyue aut Yu, Dingjia aut Yang, Wei aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 29. Sept. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:29 month:09 https://dx.doi.org/10.1186/s13046-023-02815-w kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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 42 2023 1 29 09
spelling	10.1186/s13046-023-02815-w doi (DE-627)SPR053239547 (SPR)s13046-023-02815-w-e DE-627 ger DE-627 rakwb eng Sun, Ting verfasserin aut Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Chimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part to immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of lactate inducing the formation of immunosuppressive microenvironment remains to be further explored. Methods Immunocyte subpopulations and molecular characteristics were analyzed in the orthotopic xenografts of nude mice using flow cytometry assay and immunohistochemical staining after oxamate, a lactate dehydrogenase A (LDHA) inhibitor, and control T or CAR-T cells injection alone or in combination. RT-qPCR, western blot, flow cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation and ELISA were performed to measure the effect of lactate on the regulation of CD39, CD73 and CCR8 in cultured glioma stem cells, CD4 + T cells or macrophages. Results Oxamate promoted immune activation of tumor-infiltrating CAR-T cells through altering the phenotypes of immune molecules and increasing regulatory T (Treg) cells infiltration in a glioblastoma mouse model. Lactate accumulation within cells upregulated CD39, CD73 and CCR8 expressions in both lactate-treated cells and glioma stem cells-co-cultured CD4 + T cells and macrophages, and intracellular lactate directly elevated the activities of these gene promotors through histone H3K18 lactylation. Conclusions Utilizing lactate generation inhibitor not only reprogramed glucose metabolism of cancer stem cells, but also alleviated immunosuppression of tumor microenvironment and reduced tumor-infiltrating CAR-Treg cells, which may be a potential strategy to enhance CAR-T function in glioblastoma therapy. CAR-T (dpeaa)DE-He213 Glioblastoma (dpeaa)DE-He213 Histone lactylation (dpeaa)DE-He213 Ectonucleotidases (dpeaa)DE-He213 CCR8 (dpeaa)DE-He213 Liu, Bin aut Li, Yanyan aut Wu, Jie aut Cao, Yufei aut Yang, Shuangyu aut Tan, Huiling aut Cai, Lize aut Zhang, Shiqi aut Qi, Xinyue aut Yu, Dingjia aut Yang, Wei aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 29. Sept. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:29 month:09 https://dx.doi.org/10.1186/s13046-023-02815-w kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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 42 2023 1 29 09
allfields_unstemmed	10.1186/s13046-023-02815-w doi (DE-627)SPR053239547 (SPR)s13046-023-02815-w-e DE-627 ger DE-627 rakwb eng Sun, Ting verfasserin aut Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Chimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part to immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of lactate inducing the formation of immunosuppressive microenvironment remains to be further explored. Methods Immunocyte subpopulations and molecular characteristics were analyzed in the orthotopic xenografts of nude mice using flow cytometry assay and immunohistochemical staining after oxamate, a lactate dehydrogenase A (LDHA) inhibitor, and control T or CAR-T cells injection alone or in combination. RT-qPCR, western blot, flow cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation and ELISA were performed to measure the effect of lactate on the regulation of CD39, CD73 and CCR8 in cultured glioma stem cells, CD4 + T cells or macrophages. Results Oxamate promoted immune activation of tumor-infiltrating CAR-T cells through altering the phenotypes of immune molecules and increasing regulatory T (Treg) cells infiltration in a glioblastoma mouse model. Lactate accumulation within cells upregulated CD39, CD73 and CCR8 expressions in both lactate-treated cells and glioma stem cells-co-cultured CD4 + T cells and macrophages, and intracellular lactate directly elevated the activities of these gene promotors through histone H3K18 lactylation. Conclusions Utilizing lactate generation inhibitor not only reprogramed glucose metabolism of cancer stem cells, but also alleviated immunosuppression of tumor microenvironment and reduced tumor-infiltrating CAR-Treg cells, which may be a potential strategy to enhance CAR-T function in glioblastoma therapy. CAR-T (dpeaa)DE-He213 Glioblastoma (dpeaa)DE-He213 Histone lactylation (dpeaa)DE-He213 Ectonucleotidases (dpeaa)DE-He213 CCR8 (dpeaa)DE-He213 Liu, Bin aut Li, Yanyan aut Wu, Jie aut Cao, Yufei aut Yang, Shuangyu aut Tan, Huiling aut Cai, Lize aut Zhang, Shiqi aut Qi, Xinyue aut Yu, Dingjia aut Yang, Wei aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 29. Sept. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:29 month:09 https://dx.doi.org/10.1186/s13046-023-02815-w kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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 42 2023 1 29 09
allfieldsGer	10.1186/s13046-023-02815-w doi (DE-627)SPR053239547 (SPR)s13046-023-02815-w-e DE-627 ger DE-627 rakwb eng Sun, Ting verfasserin aut Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Chimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part to immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of lactate inducing the formation of immunosuppressive microenvironment remains to be further explored. Methods Immunocyte subpopulations and molecular characteristics were analyzed in the orthotopic xenografts of nude mice using flow cytometry assay and immunohistochemical staining after oxamate, a lactate dehydrogenase A (LDHA) inhibitor, and control T or CAR-T cells injection alone or in combination. RT-qPCR, western blot, flow cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation and ELISA were performed to measure the effect of lactate on the regulation of CD39, CD73 and CCR8 in cultured glioma stem cells, CD4 + T cells or macrophages. Results Oxamate promoted immune activation of tumor-infiltrating CAR-T cells through altering the phenotypes of immune molecules and increasing regulatory T (Treg) cells infiltration in a glioblastoma mouse model. Lactate accumulation within cells upregulated CD39, CD73 and CCR8 expressions in both lactate-treated cells and glioma stem cells-co-cultured CD4 + T cells and macrophages, and intracellular lactate directly elevated the activities of these gene promotors through histone H3K18 lactylation. Conclusions Utilizing lactate generation inhibitor not only reprogramed glucose metabolism of cancer stem cells, but also alleviated immunosuppression of tumor microenvironment and reduced tumor-infiltrating CAR-Treg cells, which may be a potential strategy to enhance CAR-T function in glioblastoma therapy. CAR-T (dpeaa)DE-He213 Glioblastoma (dpeaa)DE-He213 Histone lactylation (dpeaa)DE-He213 Ectonucleotidases (dpeaa)DE-He213 CCR8 (dpeaa)DE-He213 Liu, Bin aut Li, Yanyan aut Wu, Jie aut Cao, Yufei aut Yang, Shuangyu aut Tan, Huiling aut Cai, Lize aut Zhang, Shiqi aut Qi, Xinyue aut Yu, Dingjia aut Yang, Wei aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 29. Sept. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:29 month:09 https://dx.doi.org/10.1186/s13046-023-02815-w kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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 42 2023 1 29 09
allfieldsSound	10.1186/s13046-023-02815-w doi (DE-627)SPR053239547 (SPR)s13046-023-02815-w-e DE-627 ger DE-627 rakwb eng Sun, Ting verfasserin aut Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Background Chimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part to immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of lactate inducing the formation of immunosuppressive microenvironment remains to be further explored. Methods Immunocyte subpopulations and molecular characteristics were analyzed in the orthotopic xenografts of nude mice using flow cytometry assay and immunohistochemical staining after oxamate, a lactate dehydrogenase A (LDHA) inhibitor, and control T or CAR-T cells injection alone or in combination. RT-qPCR, western blot, flow cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation and ELISA were performed to measure the effect of lactate on the regulation of CD39, CD73 and CCR8 in cultured glioma stem cells, CD4 + T cells or macrophages. Results Oxamate promoted immune activation of tumor-infiltrating CAR-T cells through altering the phenotypes of immune molecules and increasing regulatory T (Treg) cells infiltration in a glioblastoma mouse model. Lactate accumulation within cells upregulated CD39, CD73 and CCR8 expressions in both lactate-treated cells and glioma stem cells-co-cultured CD4 + T cells and macrophages, and intracellular lactate directly elevated the activities of these gene promotors through histone H3K18 lactylation. Conclusions Utilizing lactate generation inhibitor not only reprogramed glucose metabolism of cancer stem cells, but also alleviated immunosuppression of tumor microenvironment and reduced tumor-infiltrating CAR-Treg cells, which may be a potential strategy to enhance CAR-T function in glioblastoma therapy. CAR-T (dpeaa)DE-He213 Glioblastoma (dpeaa)DE-He213 Histone lactylation (dpeaa)DE-He213 Ectonucleotidases (dpeaa)DE-He213 CCR8 (dpeaa)DE-He213 Liu, Bin aut Li, Yanyan aut Wu, Jie aut Cao, Yufei aut Yang, Shuangyu aut Tan, Huiling aut Cai, Lize aut Zhang, Shiqi aut Qi, Xinyue aut Yu, Dingjia aut Yang, Wei aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 29. Sept. (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:29 month:09 https://dx.doi.org/10.1186/s13046-023-02815-w kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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 42 2023 1 29 09
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author	Sun, Ting
spellingShingle	Sun, Ting misc CAR-T misc Glioblastoma misc Histone lactylation misc Ectonucleotidases misc CCR8 Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation
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topic_title	Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation CAR-T (dpeaa)DE-He213 Glioblastoma (dpeaa)DE-He213 Histone lactylation (dpeaa)DE-He213 Ectonucleotidases (dpeaa)DE-He213 CCR8 (dpeaa)DE-He213
topic	misc CAR-T misc Glioblastoma misc Histone lactylation misc Ectonucleotidases misc CCR8
topic_unstemmed	misc CAR-T misc Glioblastoma misc Histone lactylation misc Ectonucleotidases misc CCR8
topic_browse	misc CAR-T misc Glioblastoma misc Histone lactylation misc Ectonucleotidases misc CCR8
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title	Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation
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title_full	Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation
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author_browse	Sun, Ting Liu, Bin Li, Yanyan Wu, Jie Cao, Yufei Yang, Shuangyu Tan, Huiling Cai, Lize Zhang, Shiqi Qi, Xinyue Yu, Dingjia Yang, Wei
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title_sort	oxamate enhances the efficacy of car-t therapy against glioblastoma via suppressing ectonucleotidases and ccr8 lactylation
title_auth	Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation
abstract	Background Chimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part to immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of lactate inducing the formation of immunosuppressive microenvironment remains to be further explored. Methods Immunocyte subpopulations and molecular characteristics were analyzed in the orthotopic xenografts of nude mice using flow cytometry assay and immunohistochemical staining after oxamate, a lactate dehydrogenase A (LDHA) inhibitor, and control T or CAR-T cells injection alone or in combination. RT-qPCR, western blot, flow cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation and ELISA were performed to measure the effect of lactate on the regulation of CD39, CD73 and CCR8 in cultured glioma stem cells, CD4 + T cells or macrophages. Results Oxamate promoted immune activation of tumor-infiltrating CAR-T cells through altering the phenotypes of immune molecules and increasing regulatory T (Treg) cells infiltration in a glioblastoma mouse model. Lactate accumulation within cells upregulated CD39, CD73 and CCR8 expressions in both lactate-treated cells and glioma stem cells-co-cultured CD4 + T cells and macrophages, and intracellular lactate directly elevated the activities of these gene promotors through histone H3K18 lactylation. Conclusions Utilizing lactate generation inhibitor not only reprogramed glucose metabolism of cancer stem cells, but also alleviated immunosuppression of tumor microenvironment and reduced tumor-infiltrating CAR-Treg cells, which may be a potential strategy to enhance CAR-T function in glioblastoma therapy. © The Author(s) 2023
abstractGer	Background Chimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part to immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of lactate inducing the formation of immunosuppressive microenvironment remains to be further explored. Methods Immunocyte subpopulations and molecular characteristics were analyzed in the orthotopic xenografts of nude mice using flow cytometry assay and immunohistochemical staining after oxamate, a lactate dehydrogenase A (LDHA) inhibitor, and control T or CAR-T cells injection alone or in combination. RT-qPCR, western blot, flow cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation and ELISA were performed to measure the effect of lactate on the regulation of CD39, CD73 and CCR8 in cultured glioma stem cells, CD4 + T cells or macrophages. Results Oxamate promoted immune activation of tumor-infiltrating CAR-T cells through altering the phenotypes of immune molecules and increasing regulatory T (Treg) cells infiltration in a glioblastoma mouse model. Lactate accumulation within cells upregulated CD39, CD73 and CCR8 expressions in both lactate-treated cells and glioma stem cells-co-cultured CD4 + T cells and macrophages, and intracellular lactate directly elevated the activities of these gene promotors through histone H3K18 lactylation. Conclusions Utilizing lactate generation inhibitor not only reprogramed glucose metabolism of cancer stem cells, but also alleviated immunosuppression of tumor microenvironment and reduced tumor-infiltrating CAR-Treg cells, which may be a potential strategy to enhance CAR-T function in glioblastoma therapy. © The Author(s) 2023
abstract_unstemmed	Background Chimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part to immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of lactate inducing the formation of immunosuppressive microenvironment remains to be further explored. Methods Immunocyte subpopulations and molecular characteristics were analyzed in the orthotopic xenografts of nude mice using flow cytometry assay and immunohistochemical staining after oxamate, a lactate dehydrogenase A (LDHA) inhibitor, and control T or CAR-T cells injection alone or in combination. RT-qPCR, western blot, flow cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation and ELISA were performed to measure the effect of lactate on the regulation of CD39, CD73 and CCR8 in cultured glioma stem cells, CD4 + T cells or macrophages. Results Oxamate promoted immune activation of tumor-infiltrating CAR-T cells through altering the phenotypes of immune molecules and increasing regulatory T (Treg) cells infiltration in a glioblastoma mouse model. Lactate accumulation within cells upregulated CD39, CD73 and CCR8 expressions in both lactate-treated cells and glioma stem cells-co-cultured CD4 + T cells and macrophages, and intracellular lactate directly elevated the activities of these gene promotors through histone H3K18 lactylation. Conclusions Utilizing lactate generation inhibitor not only reprogramed glucose metabolism of cancer stem cells, but also alleviated immunosuppression of tumor microenvironment and reduced tumor-infiltrating CAR-Treg cells, which may be a potential strategy to enhance CAR-T function in glioblastoma therapy. © The Author(s) 2023
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title_short	Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation
url	https://dx.doi.org/10.1186/s13046-023-02815-w
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author2	Liu, Bin Li, Yanyan Wu, Jie Cao, Yufei Yang, Shuangyu Tan, Huiling Cai, Lize Zhang, Shiqi Qi, Xinyue Yu, Dingjia Yang, Wei
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up_date	2024-07-03T18:04:39.726Z
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Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of lactate inducing the formation of immunosuppressive microenvironment remains to be further explored. Methods Immunocyte subpopulations and molecular characteristics were analyzed in the orthotopic xenografts of nude mice using flow cytometry assay and immunohistochemical staining after oxamate, a lactate dehydrogenase A (LDHA) inhibitor, and control T or CAR-T cells injection alone or in combination. RT-qPCR, western blot, flow cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation and ELISA were performed to measure the effect of lactate on the regulation of CD39, CD73 and CCR8 in cultured glioma stem cells, CD4 + T cells or macrophages. Results Oxamate promoted immune activation of tumor-infiltrating CAR-T cells through altering the phenotypes of immune molecules and increasing regulatory T (Treg) cells infiltration in a glioblastoma mouse model. Lactate accumulation within cells upregulated CD39, CD73 and CCR8 expressions in both lactate-treated cells and glioma stem cells-co-cultured CD4 + T cells and macrophages, and intracellular lactate directly elevated the activities of these gene promotors through histone H3K18 lactylation. 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Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation

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