S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function
Abstract Background The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. This study endeavors to delve into the potential peripheral biomarkers ca...
Ausführliche Beschreibung
Autor*in: |
Xiaoxuan Tu [verfasserIn] Longxian Chen [verfasserIn] Yi Zheng [verfasserIn] Chenglin Mu [verfasserIn] Zhiwei Zhang [verfasserIn] Feiyu Wang [verfasserIn] Yiqing Ren [verfasserIn] Yingxin Duan [verfasserIn] Hangyu Zhang [verfasserIn] Zhou Tong [verfasserIn] Lulu Liu [verfasserIn] Xunqi Sun [verfasserIn] Peng Zhao [verfasserIn] Lie Wang [verfasserIn] Xinhua Feng [verfasserIn] Weijia Fang [verfasserIn] Xia Liu [verfasserIn] |
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E-Artikel |
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Sprache: |
Englisch |
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2024 |
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In: Journal of Experimental & Clinical Cancer Research - BMC, 2008, 43(2024), 1, Seite 22 |
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Übergeordnetes Werk: |
volume:43 ; year:2024 ; number:1 ; pages:22 |
Links: |
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DOI / URN: |
10.1186/s13046-024-02985-1 |
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Katalog-ID: |
DOAJ092302971 |
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520 | |a Abstract Background The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. This study endeavors to delve into the potential peripheral biomarkers capable of prognosticating efficacy in HCC patients who are poised to receive anti-PD-1 monotherapy within the phase III clinical trial, KEYNOTE394. Additionally, we sought to elucidate the underlying molecular mechanisms for resistance to immune checkpoint blockade (ICB) and propose innovative combination immunotherapy strategies for future clinical application. Methods Patient blood samples were collected for single-cell RNA sequencing to evaluate the immune cell signature before receiving ICB therapy. Subsequently, in vitro assays and in vivo murine model experiments were conducted to validate the mechanism that S100A9+CD14+ monocytes play a role in ICB resistance. Results Our study demonstrates a notable enrichment of S100A9+CD14+ monocytes in the peripheral blood of patients exhibiting suboptimal responses to anti-PD-1 therapy. Moreover, we identified the Mono_S100A9 signature as a predictive biomarker, indicative of reduced efficacy in immunotherapy and decreased survival benefits across various tumor types. Mechanistically, S100A9 activates PD-L1 transcription by directly binding to the CD274 (PD-L1) gene promoter, thereby suppressing T-cell proliferation and cytotoxicity via the PD-1/PD-L1 axis, consequently diminishing the therapeutic effectiveness of subsequent anti-PD-1 treatments. Furthermore, our in vivo studies revealed that inhibiting S100A9 can synergistically enhance the efficacy of anti-PD-1 drugs in the eradication of hepatocellular carcinoma. Conclusions Our study underscores the significance of S100A9+CD14+ monocytes in predicting inadequate response to ICB treatment and provides insights into the monocyte cell-intrinsic mechanisms of resistance to ICB therapy. We also propose a combined therapeutic approach to enhance ICB efficacy by targeting S100A9. | ||
650 | 4 | |a Hepatocellular carcinoma | |
650 | 4 | |a Anti-PD-1 monotherapy | |
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653 | 0 | |a Neoplasms. Tumors. Oncology. Including cancer and carcinogens | |
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700 | 0 | |a Xia Liu |e verfasserin |4 aut | |
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10.1186/s13046-024-02985-1 doi (DE-627)DOAJ092302971 (DE-599)DOAJ51d8672f00fb48fbb243daddc542d21b DE-627 ger DE-627 rakwb eng RC254-282 Xiaoxuan Tu verfasserin aut S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. This study endeavors to delve into the potential peripheral biomarkers capable of prognosticating efficacy in HCC patients who are poised to receive anti-PD-1 monotherapy within the phase III clinical trial, KEYNOTE394. Additionally, we sought to elucidate the underlying molecular mechanisms for resistance to immune checkpoint blockade (ICB) and propose innovative combination immunotherapy strategies for future clinical application. Methods Patient blood samples were collected for single-cell RNA sequencing to evaluate the immune cell signature before receiving ICB therapy. Subsequently, in vitro assays and in vivo murine model experiments were conducted to validate the mechanism that S100A9+CD14+ monocytes play a role in ICB resistance. Results Our study demonstrates a notable enrichment of S100A9+CD14+ monocytes in the peripheral blood of patients exhibiting suboptimal responses to anti-PD-1 therapy. Moreover, we identified the Mono_S100A9 signature as a predictive biomarker, indicative of reduced efficacy in immunotherapy and decreased survival benefits across various tumor types. Mechanistically, S100A9 activates PD-L1 transcription by directly binding to the CD274 (PD-L1) gene promoter, thereby suppressing T-cell proliferation and cytotoxicity via the PD-1/PD-L1 axis, consequently diminishing the therapeutic effectiveness of subsequent anti-PD-1 treatments. Furthermore, our in vivo studies revealed that inhibiting S100A9 can synergistically enhance the efficacy of anti-PD-1 drugs in the eradication of hepatocellular carcinoma. Conclusions Our study underscores the significance of S100A9+CD14+ monocytes in predicting inadequate response to ICB treatment and provides insights into the monocyte cell-intrinsic mechanisms of resistance to ICB therapy. We also propose a combined therapeutic approach to enhance ICB efficacy by targeting S100A9. Hepatocellular carcinoma Anti-PD-1 monotherapy Biomarker Single-cell RNA sequencing S100A9+CD14+ monocyte Neoplasms. Tumors. Oncology. Including cancer and carcinogens Longxian Chen verfasserin aut Yi Zheng verfasserin aut Chenglin Mu verfasserin aut Zhiwei Zhang verfasserin aut Feiyu Wang verfasserin aut Yiqing Ren verfasserin aut Yingxin Duan verfasserin aut Hangyu Zhang verfasserin aut Zhou Tong verfasserin aut Lulu Liu verfasserin aut Xunqi Sun verfasserin aut Peng Zhao verfasserin aut Lie Wang verfasserin aut Xinhua Feng verfasserin aut Weijia Fang verfasserin aut Xia Liu verfasserin aut In Journal of Experimental & Clinical Cancer Research BMC, 2008 43(2024), 1, Seite 22 (DE-627)568921380 (DE-600)2430698-8 17569966 nnns volume:43 year:2024 number:1 pages:22 https://doi.org/10.1186/s13046-024-02985-1 kostenfrei https://doaj.org/article/51d8672f00fb48fbb243daddc542d21b kostenfrei https://doi.org/10.1186/s13046-024-02985-1 kostenfrei https://doaj.org/toc/1756-9966 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_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 43 2024 1 22 |
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10.1186/s13046-024-02985-1 doi (DE-627)DOAJ092302971 (DE-599)DOAJ51d8672f00fb48fbb243daddc542d21b DE-627 ger DE-627 rakwb eng RC254-282 Xiaoxuan Tu verfasserin aut S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. This study endeavors to delve into the potential peripheral biomarkers capable of prognosticating efficacy in HCC patients who are poised to receive anti-PD-1 monotherapy within the phase III clinical trial, KEYNOTE394. Additionally, we sought to elucidate the underlying molecular mechanisms for resistance to immune checkpoint blockade (ICB) and propose innovative combination immunotherapy strategies for future clinical application. Methods Patient blood samples were collected for single-cell RNA sequencing to evaluate the immune cell signature before receiving ICB therapy. Subsequently, in vitro assays and in vivo murine model experiments were conducted to validate the mechanism that S100A9+CD14+ monocytes play a role in ICB resistance. Results Our study demonstrates a notable enrichment of S100A9+CD14+ monocytes in the peripheral blood of patients exhibiting suboptimal responses to anti-PD-1 therapy. Moreover, we identified the Mono_S100A9 signature as a predictive biomarker, indicative of reduced efficacy in immunotherapy and decreased survival benefits across various tumor types. Mechanistically, S100A9 activates PD-L1 transcription by directly binding to the CD274 (PD-L1) gene promoter, thereby suppressing T-cell proliferation and cytotoxicity via the PD-1/PD-L1 axis, consequently diminishing the therapeutic effectiveness of subsequent anti-PD-1 treatments. Furthermore, our in vivo studies revealed that inhibiting S100A9 can synergistically enhance the efficacy of anti-PD-1 drugs in the eradication of hepatocellular carcinoma. Conclusions Our study underscores the significance of S100A9+CD14+ monocytes in predicting inadequate response to ICB treatment and provides insights into the monocyte cell-intrinsic mechanisms of resistance to ICB therapy. We also propose a combined therapeutic approach to enhance ICB efficacy by targeting S100A9. Hepatocellular carcinoma Anti-PD-1 monotherapy Biomarker Single-cell RNA sequencing S100A9+CD14+ monocyte Neoplasms. Tumors. Oncology. Including cancer and carcinogens Longxian Chen verfasserin aut Yi Zheng verfasserin aut Chenglin Mu verfasserin aut Zhiwei Zhang verfasserin aut Feiyu Wang verfasserin aut Yiqing Ren verfasserin aut Yingxin Duan verfasserin aut Hangyu Zhang verfasserin aut Zhou Tong verfasserin aut Lulu Liu verfasserin aut Xunqi Sun verfasserin aut Peng Zhao verfasserin aut Lie Wang verfasserin aut Xinhua Feng verfasserin aut Weijia Fang verfasserin aut Xia Liu verfasserin aut In Journal of Experimental & Clinical Cancer Research BMC, 2008 43(2024), 1, Seite 22 (DE-627)568921380 (DE-600)2430698-8 17569966 nnns volume:43 year:2024 number:1 pages:22 https://doi.org/10.1186/s13046-024-02985-1 kostenfrei https://doaj.org/article/51d8672f00fb48fbb243daddc542d21b kostenfrei https://doi.org/10.1186/s13046-024-02985-1 kostenfrei https://doaj.org/toc/1756-9966 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_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 43 2024 1 22 |
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10.1186/s13046-024-02985-1 doi (DE-627)DOAJ092302971 (DE-599)DOAJ51d8672f00fb48fbb243daddc542d21b DE-627 ger DE-627 rakwb eng RC254-282 Xiaoxuan Tu verfasserin aut S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. This study endeavors to delve into the potential peripheral biomarkers capable of prognosticating efficacy in HCC patients who are poised to receive anti-PD-1 monotherapy within the phase III clinical trial, KEYNOTE394. Additionally, we sought to elucidate the underlying molecular mechanisms for resistance to immune checkpoint blockade (ICB) and propose innovative combination immunotherapy strategies for future clinical application. Methods Patient blood samples were collected for single-cell RNA sequencing to evaluate the immune cell signature before receiving ICB therapy. Subsequently, in vitro assays and in vivo murine model experiments were conducted to validate the mechanism that S100A9+CD14+ monocytes play a role in ICB resistance. Results Our study demonstrates a notable enrichment of S100A9+CD14+ monocytes in the peripheral blood of patients exhibiting suboptimal responses to anti-PD-1 therapy. Moreover, we identified the Mono_S100A9 signature as a predictive biomarker, indicative of reduced efficacy in immunotherapy and decreased survival benefits across various tumor types. Mechanistically, S100A9 activates PD-L1 transcription by directly binding to the CD274 (PD-L1) gene promoter, thereby suppressing T-cell proliferation and cytotoxicity via the PD-1/PD-L1 axis, consequently diminishing the therapeutic effectiveness of subsequent anti-PD-1 treatments. Furthermore, our in vivo studies revealed that inhibiting S100A9 can synergistically enhance the efficacy of anti-PD-1 drugs in the eradication of hepatocellular carcinoma. Conclusions Our study underscores the significance of S100A9+CD14+ monocytes in predicting inadequate response to ICB treatment and provides insights into the monocyte cell-intrinsic mechanisms of resistance to ICB therapy. We also propose a combined therapeutic approach to enhance ICB efficacy by targeting S100A9. Hepatocellular carcinoma Anti-PD-1 monotherapy Biomarker Single-cell RNA sequencing S100A9+CD14+ monocyte Neoplasms. Tumors. Oncology. Including cancer and carcinogens Longxian Chen verfasserin aut Yi Zheng verfasserin aut Chenglin Mu verfasserin aut Zhiwei Zhang verfasserin aut Feiyu Wang verfasserin aut Yiqing Ren verfasserin aut Yingxin Duan verfasserin aut Hangyu Zhang verfasserin aut Zhou Tong verfasserin aut Lulu Liu verfasserin aut Xunqi Sun verfasserin aut Peng Zhao verfasserin aut Lie Wang verfasserin aut Xinhua Feng verfasserin aut Weijia Fang verfasserin aut Xia Liu verfasserin aut In Journal of Experimental & Clinical Cancer Research BMC, 2008 43(2024), 1, Seite 22 (DE-627)568921380 (DE-600)2430698-8 17569966 nnns volume:43 year:2024 number:1 pages:22 https://doi.org/10.1186/s13046-024-02985-1 kostenfrei https://doaj.org/article/51d8672f00fb48fbb243daddc542d21b kostenfrei https://doi.org/10.1186/s13046-024-02985-1 kostenfrei https://doaj.org/toc/1756-9966 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_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 43 2024 1 22 |
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10.1186/s13046-024-02985-1 doi (DE-627)DOAJ092302971 (DE-599)DOAJ51d8672f00fb48fbb243daddc542d21b DE-627 ger DE-627 rakwb eng RC254-282 Xiaoxuan Tu verfasserin aut S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. This study endeavors to delve into the potential peripheral biomarkers capable of prognosticating efficacy in HCC patients who are poised to receive anti-PD-1 monotherapy within the phase III clinical trial, KEYNOTE394. Additionally, we sought to elucidate the underlying molecular mechanisms for resistance to immune checkpoint blockade (ICB) and propose innovative combination immunotherapy strategies for future clinical application. Methods Patient blood samples were collected for single-cell RNA sequencing to evaluate the immune cell signature before receiving ICB therapy. Subsequently, in vitro assays and in vivo murine model experiments were conducted to validate the mechanism that S100A9+CD14+ monocytes play a role in ICB resistance. Results Our study demonstrates a notable enrichment of S100A9+CD14+ monocytes in the peripheral blood of patients exhibiting suboptimal responses to anti-PD-1 therapy. Moreover, we identified the Mono_S100A9 signature as a predictive biomarker, indicative of reduced efficacy in immunotherapy and decreased survival benefits across various tumor types. Mechanistically, S100A9 activates PD-L1 transcription by directly binding to the CD274 (PD-L1) gene promoter, thereby suppressing T-cell proliferation and cytotoxicity via the PD-1/PD-L1 axis, consequently diminishing the therapeutic effectiveness of subsequent anti-PD-1 treatments. Furthermore, our in vivo studies revealed that inhibiting S100A9 can synergistically enhance the efficacy of anti-PD-1 drugs in the eradication of hepatocellular carcinoma. Conclusions Our study underscores the significance of S100A9+CD14+ monocytes in predicting inadequate response to ICB treatment and provides insights into the monocyte cell-intrinsic mechanisms of resistance to ICB therapy. We also propose a combined therapeutic approach to enhance ICB efficacy by targeting S100A9. Hepatocellular carcinoma Anti-PD-1 monotherapy Biomarker Single-cell RNA sequencing S100A9+CD14+ monocyte Neoplasms. Tumors. Oncology. Including cancer and carcinogens Longxian Chen verfasserin aut Yi Zheng verfasserin aut Chenglin Mu verfasserin aut Zhiwei Zhang verfasserin aut Feiyu Wang verfasserin aut Yiqing Ren verfasserin aut Yingxin Duan verfasserin aut Hangyu Zhang verfasserin aut Zhou Tong verfasserin aut Lulu Liu verfasserin aut Xunqi Sun verfasserin aut Peng Zhao verfasserin aut Lie Wang verfasserin aut Xinhua Feng verfasserin aut Weijia Fang verfasserin aut Xia Liu verfasserin aut In Journal of Experimental & Clinical Cancer Research BMC, 2008 43(2024), 1, Seite 22 (DE-627)568921380 (DE-600)2430698-8 17569966 nnns volume:43 year:2024 number:1 pages:22 https://doi.org/10.1186/s13046-024-02985-1 kostenfrei https://doaj.org/article/51d8672f00fb48fbb243daddc542d21b kostenfrei https://doi.org/10.1186/s13046-024-02985-1 kostenfrei https://doaj.org/toc/1756-9966 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_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 43 2024 1 22 |
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RC254-282 S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function Hepatocellular carcinoma Anti-PD-1 monotherapy Biomarker Single-cell RNA sequencing S100A9+CD14+ monocyte |
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misc RC254-282 misc Hepatocellular carcinoma misc Anti-PD-1 monotherapy misc Biomarker misc Single-cell RNA sequencing misc S100A9+CD14+ monocyte misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
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misc RC254-282 misc Hepatocellular carcinoma misc Anti-PD-1 monotherapy misc Biomarker misc Single-cell RNA sequencing misc S100A9+CD14+ monocyte misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
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S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function |
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S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function |
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Xiaoxuan Tu |
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Xiaoxuan Tu Longxian Chen Yi Zheng Chenglin Mu Zhiwei Zhang Feiyu Wang Yiqing Ren Yingxin Duan Hangyu Zhang Zhou Tong Lulu Liu Xunqi Sun Peng Zhao Lie Wang Xinhua Feng Weijia Fang Xia Liu |
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s100a9+cd14+ monocytes contribute to anti-pd-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating t cell-mediated antitumor function |
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S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function |
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Abstract Background The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. This study endeavors to delve into the potential peripheral biomarkers capable of prognosticating efficacy in HCC patients who are poised to receive anti-PD-1 monotherapy within the phase III clinical trial, KEYNOTE394. Additionally, we sought to elucidate the underlying molecular mechanisms for resistance to immune checkpoint blockade (ICB) and propose innovative combination immunotherapy strategies for future clinical application. Methods Patient blood samples were collected for single-cell RNA sequencing to evaluate the immune cell signature before receiving ICB therapy. Subsequently, in vitro assays and in vivo murine model experiments were conducted to validate the mechanism that S100A9+CD14+ monocytes play a role in ICB resistance. Results Our study demonstrates a notable enrichment of S100A9+CD14+ monocytes in the peripheral blood of patients exhibiting suboptimal responses to anti-PD-1 therapy. Moreover, we identified the Mono_S100A9 signature as a predictive biomarker, indicative of reduced efficacy in immunotherapy and decreased survival benefits across various tumor types. Mechanistically, S100A9 activates PD-L1 transcription by directly binding to the CD274 (PD-L1) gene promoter, thereby suppressing T-cell proliferation and cytotoxicity via the PD-1/PD-L1 axis, consequently diminishing the therapeutic effectiveness of subsequent anti-PD-1 treatments. Furthermore, our in vivo studies revealed that inhibiting S100A9 can synergistically enhance the efficacy of anti-PD-1 drugs in the eradication of hepatocellular carcinoma. Conclusions Our study underscores the significance of S100A9+CD14+ monocytes in predicting inadequate response to ICB treatment and provides insights into the monocyte cell-intrinsic mechanisms of resistance to ICB therapy. We also propose a combined therapeutic approach to enhance ICB efficacy by targeting S100A9. |
abstractGer |
Abstract Background The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. This study endeavors to delve into the potential peripheral biomarkers capable of prognosticating efficacy in HCC patients who are poised to receive anti-PD-1 monotherapy within the phase III clinical trial, KEYNOTE394. Additionally, we sought to elucidate the underlying molecular mechanisms for resistance to immune checkpoint blockade (ICB) and propose innovative combination immunotherapy strategies for future clinical application. Methods Patient blood samples were collected for single-cell RNA sequencing to evaluate the immune cell signature before receiving ICB therapy. Subsequently, in vitro assays and in vivo murine model experiments were conducted to validate the mechanism that S100A9+CD14+ monocytes play a role in ICB resistance. Results Our study demonstrates a notable enrichment of S100A9+CD14+ monocytes in the peripheral blood of patients exhibiting suboptimal responses to anti-PD-1 therapy. Moreover, we identified the Mono_S100A9 signature as a predictive biomarker, indicative of reduced efficacy in immunotherapy and decreased survival benefits across various tumor types. Mechanistically, S100A9 activates PD-L1 transcription by directly binding to the CD274 (PD-L1) gene promoter, thereby suppressing T-cell proliferation and cytotoxicity via the PD-1/PD-L1 axis, consequently diminishing the therapeutic effectiveness of subsequent anti-PD-1 treatments. Furthermore, our in vivo studies revealed that inhibiting S100A9 can synergistically enhance the efficacy of anti-PD-1 drugs in the eradication of hepatocellular carcinoma. Conclusions Our study underscores the significance of S100A9+CD14+ monocytes in predicting inadequate response to ICB treatment and provides insights into the monocyte cell-intrinsic mechanisms of resistance to ICB therapy. We also propose a combined therapeutic approach to enhance ICB efficacy by targeting S100A9. |
abstract_unstemmed |
Abstract Background The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. This study endeavors to delve into the potential peripheral biomarkers capable of prognosticating efficacy in HCC patients who are poised to receive anti-PD-1 monotherapy within the phase III clinical trial, KEYNOTE394. Additionally, we sought to elucidate the underlying molecular mechanisms for resistance to immune checkpoint blockade (ICB) and propose innovative combination immunotherapy strategies for future clinical application. Methods Patient blood samples were collected for single-cell RNA sequencing to evaluate the immune cell signature before receiving ICB therapy. Subsequently, in vitro assays and in vivo murine model experiments were conducted to validate the mechanism that S100A9+CD14+ monocytes play a role in ICB resistance. Results Our study demonstrates a notable enrichment of S100A9+CD14+ monocytes in the peripheral blood of patients exhibiting suboptimal responses to anti-PD-1 therapy. Moreover, we identified the Mono_S100A9 signature as a predictive biomarker, indicative of reduced efficacy in immunotherapy and decreased survival benefits across various tumor types. Mechanistically, S100A9 activates PD-L1 transcription by directly binding to the CD274 (PD-L1) gene promoter, thereby suppressing T-cell proliferation and cytotoxicity via the PD-1/PD-L1 axis, consequently diminishing the therapeutic effectiveness of subsequent anti-PD-1 treatments. Furthermore, our in vivo studies revealed that inhibiting S100A9 can synergistically enhance the efficacy of anti-PD-1 drugs in the eradication of hepatocellular carcinoma. Conclusions Our study underscores the significance of S100A9+CD14+ monocytes in predicting inadequate response to ICB treatment and provides insights into the monocyte cell-intrinsic mechanisms of resistance to ICB therapy. We also propose a combined therapeutic approach to enhance ICB efficacy by targeting S100A9. |
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S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function |
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