Actionable heterogeneity of hepatocellular carcinoma therapy-induced senescence

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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Main Authors: 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
Format: Article
Language:English
Published: Springer 2025-05-01
Series:Cancer Immunology, Immunotherapy
Subjects:
Senescence
Hepatocellular carcinoma
Immunotherapy
Immunology
Online Access:https://doi.org/10.1007/s00262-025-04060-w
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Summary: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.
ISSN:1432-0851

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