Actionable heterogeneity of hepatocellular carcinoma therapy-induced senescence
Abstract Therapy-induced senescence (TIS) is a stable cell cycle arrest in cancerous cells favoring immune control upon immune cell recruitment and activation via a senescence-associated secretory phenotype (SASP). Numerous studies have investigated the therapeutic applicability of TIS in hepatocell...
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| Language: | English |
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Springer
2025-05-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-025-04060-w |
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| author | Pujan Engels Andras Szolek Sebastian Hörner Georgios Vavouras Syrigos Kim Hebbel Michelle Schmidtke Min Zhou Maria Mateo-Tortola Caroline Schönfeld Sylwia Anna Stefanczyk Katharina Wolter Sepideh Babaei Michael Schindler Manfred Claassen Daniel Dauch Lars Zender Ana Tapía-Abellán Alexander N. R. Weber |
| author_facet | Pujan Engels Andras Szolek Sebastian Hörner Georgios Vavouras Syrigos Kim Hebbel Michelle Schmidtke Min Zhou Maria Mateo-Tortola Caroline Schönfeld Sylwia Anna Stefanczyk Katharina Wolter Sepideh Babaei Michael Schindler Manfred Claassen Daniel Dauch Lars Zender Ana Tapía-Abellán Alexander N. R. Weber |
| author_sort | Pujan Engels |
| collection | DOAJ |
| description | Abstract Therapy-induced senescence (TIS) is a stable cell cycle arrest in cancerous cells favoring immune control upon immune cell recruitment and activation via a senescence-associated secretory phenotype (SASP). Numerous studies have investigated the therapeutic applicability of TIS in hepatocellular carcinoma (HCC), a frequent cancer with high morbidity and mortality. Despite these efforts, a comprehensive understanding of how TIS may expose vulnerabilities specifically for immunotherapies, a potent means of cancer therapy, in HCC remains incomplete. Therefore, we conducted systematic studies to carefully characterize actionable and shared SASP- or other senescence-associated molecular parameters of TIS. We systematically compared the TIS inducers, etoposide and alisertib with a novel TIS inducer, CX5461, for their effects on SASP, surfaceome and innate immune clearance of representative human HCC cell lines. Surprisingly, all three compounds induced both metastasis surface antigens but also immunotherapeutically tractable antigens like CD95 (Fas), CD276 (B7-H3) and CD340 (Her2). This was verified in four representative HCC cell lines and publicly available datasets of HCC. Interestingly, alisertib, etoposide and CX5461 rendered senescent HCC vulnerable to be targeted by either T-cell-engaging bispecific antibodies or CAR NK cells. Collectively, our study indicates that heterogenous, but selective features of HCC senescence may be exploited by different immunotherapeutic approaches. |
| format | Article |
| id | doaj-art-de273bfd44cd4eb8b79cc0b75ffa2f14 |
| institution | DOAJ |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-de273bfd44cd4eb8b79cc0b75ffa2f142025-08-20T02:39:44ZengSpringerCancer Immunology, Immunotherapy1432-08512025-05-0174711310.1007/s00262-025-04060-wActionable heterogeneity of hepatocellular carcinoma therapy-induced senescencePujan Engels0Andras Szolek1Sebastian Hörner2Georgios Vavouras Syrigos3Kim Hebbel4Michelle Schmidtke5Min Zhou6Maria Mateo-Tortola7Caroline Schönfeld8Sylwia Anna Stefanczyk9Katharina Wolter10Sepideh Babaei11Michael Schindler12Manfred Claassen13Daniel Dauch14Lars Zender15Ana Tapía-Abellán16Alexander N. R. Weber17Department of Innate Immunity, Institute of Immunology, University of TübingenDepartment of Innate Immunity, Institute of Immunology, University of TübingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TübingenDepartment of Medical Virology, Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital TübingenDepartment of Innate Immunity, Institute of Immunology, University of TübingenDepartment of Innate Immunity, Institute of Immunology, University of TübingenDepartment of Innate Immunity, Institute of Immunology, University of TübingenDepartment of Innate Immunity, Institute of Immunology, University of TübingenDepartment of Innate Immunity, Institute of Immunology, University of TübingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TübingeniFIT Cluster of Excellence 2180, ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of TübingenDepartment of Internal Medicine I, University Hospital TübingenDepartment of Medical Virology, Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital TübingenDepartment of Internal Medicine I, University Hospital TübingeniFIT Cluster of Excellence 2180, ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of TübingeniFIT Cluster of Excellence 2180, ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of TübingenDepartment of Innate Immunity, Institute of Immunology, University of TübingenDepartment of Innate Immunity, Institute of Immunology, University of TübingenAbstract Therapy-induced senescence (TIS) is a stable cell cycle arrest in cancerous cells favoring immune control upon immune cell recruitment and activation via a senescence-associated secretory phenotype (SASP). Numerous studies have investigated the therapeutic applicability of TIS in hepatocellular carcinoma (HCC), a frequent cancer with high morbidity and mortality. Despite these efforts, a comprehensive understanding of how TIS may expose vulnerabilities specifically for immunotherapies, a potent means of cancer therapy, in HCC remains incomplete. Therefore, we conducted systematic studies to carefully characterize actionable and shared SASP- or other senescence-associated molecular parameters of TIS. We systematically compared the TIS inducers, etoposide and alisertib with a novel TIS inducer, CX5461, for their effects on SASP, surfaceome and innate immune clearance of representative human HCC cell lines. Surprisingly, all three compounds induced both metastasis surface antigens but also immunotherapeutically tractable antigens like CD95 (Fas), CD276 (B7-H3) and CD340 (Her2). This was verified in four representative HCC cell lines and publicly available datasets of HCC. Interestingly, alisertib, etoposide and CX5461 rendered senescent HCC vulnerable to be targeted by either T-cell-engaging bispecific antibodies or CAR NK cells. Collectively, our study indicates that heterogenous, but selective features of HCC senescence may be exploited by different immunotherapeutic approaches.https://doi.org/10.1007/s00262-025-04060-wSenescenceHepatocellular carcinomaImmunotherapyImmunology |
| spellingShingle | Pujan Engels Andras Szolek Sebastian Hörner Georgios Vavouras Syrigos Kim Hebbel Michelle Schmidtke Min Zhou Maria Mateo-Tortola Caroline Schönfeld Sylwia Anna Stefanczyk Katharina Wolter Sepideh Babaei Michael Schindler Manfred Claassen Daniel Dauch Lars Zender Ana Tapía-Abellán Alexander N. R. Weber Actionable heterogeneity of hepatocellular carcinoma therapy-induced senescence Cancer Immunology, Immunotherapy Senescence Hepatocellular carcinoma Immunotherapy Immunology |
| title | Actionable heterogeneity of hepatocellular carcinoma therapy-induced senescence |
| title_full | Actionable heterogeneity of hepatocellular carcinoma therapy-induced senescence |
| title_fullStr | Actionable heterogeneity of hepatocellular carcinoma therapy-induced senescence |
| title_full_unstemmed | Actionable heterogeneity of hepatocellular carcinoma therapy-induced senescence |
| title_short | Actionable heterogeneity of hepatocellular carcinoma therapy-induced senescence |
| title_sort | actionable heterogeneity of hepatocellular carcinoma therapy induced senescence |
| topic | Senescence Hepatocellular carcinoma Immunotherapy Immunology |
| url | https://doi.org/10.1007/s00262-025-04060-w |
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