Extracellular matrix reprogramming by the YAP/TAZ/TGF-β2 axis drives immune exclusion in cholangiocarcinoma models
Marco Jessen, KyungMok Kim, Marie Tollot-Wegner, Anita Cindric Vranesic, Cagla Dönmez, Celina Junker, Tina Lehmann, Advitiya Khandelwal, Yuliya Kurlishchuk, Tom Hünniger, Christin Ritter, Evaristo Di Napoli, Shyam Krishnan Murali, Konrad Bücking, Viktoria Haug, Sabine Muth, Tracy T. Tang, Andreas Rosenwald, Markus Radsak, Donato Inverso, Tanja Deckert-Gaudig, Volker Deckert, Orlando Paciello, Björn von Eyss
Marco Jessen, KyungMok Kim, Marie Tollot-Wegner, Anita Cindric Vranesic, Cagla Dönmez, Celina Junker, Tina Lehmann, Advitiya Khandelwal, Yuliya Kurlishchuk, Tom Hünniger, Christin Ritter, Evaristo Di Napoli, Shyam Krishnan Murali, Konrad Bücking, Viktoria Haug, Sabine Muth, Tracy T. Tang, Andreas Rosenwald, Markus Radsak, Donato Inverso, Tanja Deckert-Gaudig, Volker Deckert, Orlando Paciello, Björn von Eyss
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Research Article Hepatology Oncology

Extracellular matrix reprogramming by the YAP/TAZ/TGF-β2 axis drives immune exclusion in cholangiocarcinoma models

Abstract

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, are often hyperactivated in cancer, promoting tumor progression and therapy resistance. Their oncogenic role depends on interaction with TEA domain (TEAD) transcription factors, making the TEAD-YAP/TAZ complex a promising therapeutic target. Using translational mouse models, we show here that sustained systemic depletion of YAP and TAZ (YAP/TAZ) caused severe side effects. These could be avoided through pulsed inhibition, which effectively suppressed tumor growth, even at advanced stages. We identified Tgfb2 as a critical YAP/TAZ target gene for tumor formation and demonstrated that YAP/TAZ drove T cell exclusion via activation of tissue-remodeling genes. Consequently, YAP/TAZ inhibition enhanced immune cell infiltration. However, infiltrating T cells rapidly underwent exhaustion. Combining YAP/TAZ inhibition with immune checkpoint blockade reversed this exhaustion and sensitized resistant tumors to immunotherapy. This combination reshaped the tumor microenvironment to support immune cell infiltration and activation, representing a therapeutic strategy that maximizes antitumor immunity while minimizing toxicity.

Authors

Marco Jessen, KyungMok Kim, Marie Tollot-Wegner, Anita Cindric Vranesic, Cagla Dönmez, Celina Junker, Tina Lehmann, Advitiya Khandelwal, Yuliya Kurlishchuk, Tom Hünniger, Christin Ritter, Evaristo Di Napoli, Shyam Krishnan Murali, Konrad Bücking, Viktoria Haug, Sabine Muth, Tracy T. Tang, Andreas Rosenwald, Markus Radsak, Donato Inverso, Tanja Deckert-Gaudig, Volker Deckert, Orlando Paciello, Björn von Eyss

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Figure 2

YAP/TAZ inhibition is beneficial in advanced CCA.

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YAP/TAZ inhibition is beneficial in advanced CCA. (A) Preventive model: ...
(A) Preventive model: YAP/TAZ depletion was initiated in the HDTVI N-AKT CCA model via weekly intermittent doxycycline administration. Tumors were analyzed 5 weeks after HDTVI. N, notch intracellular domain. (B) Representative gross liver images (top) and H&E-stained liver sections (bottom) from mice of the indicated genotypes are shown. Scale bars: 1 cm (livers), 2 mm (H&E). (C and D) Quantification (C) of liver-to-body weight ratios and relative tumor area (D) (shRen, n = 8; shYT1, n = 3; shYT2, n = 7). (E) Therapeutic model: YAP/TAZ depletion was transiently performed in advanced N-AKT CCA 4 and 7 weeks after HDTVI. (F) Kaplan-Meier survival curves depict early (weeks 1–7) and late (weeks 8–10) survival of control mice (shRen, n = 12) versus YAP/TAZ-depleted mice (shYT1, n = 10; shYT2, n = 13). (G) Representative livers (top) and H&E-stained liver sections are shown. The respective survival rates (in days) are indicated. Scale bars: 1 cm (livers) and 2 mm (H&E). (H and I) Quantification (I) of liver-to-body weight ratios and relative tumor area (J) (shRen, n = 12; shYT1, n = 10; shYT2, n = 13). Data represent the mean ± SEM. Statistical analyses: 1-way ANOVA with Tukey’s HSD post hoc test (C, D, H, and I) or ranked test (F).