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 1

Systemic long-term depletion of YAP/TAZ is highly detrimental.

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Systemic long-term depletion of YAP/TAZ is highly detrimental. (A) Schem...
(A) Schematic of the inducible shRNA mouse model. Ubiquitous expression of rtTA3 under the CAG promoter enables ubiquitous expression of doxycycline-inducible shRNAs targeting Yap1 and Wwtr1 (Taz). Two independent mouse lines (shYT1 and shYT2) were compared with control mice expressing an shRNA against Renilla (shRen). (B) Western blot of liver lysates confirming YAP and TAZ knockdown after 2 weeks (shYT2) or 4 weeks (shYT1) of doxycycline treatment (n = 3 per group). (C and D) Liver sections (C) stained for CK19 and Sox9; arrows indicate positive BECs (scale bars: 100 μm) and quantification (D) of BEC counts per liver area (n = 6 per group). (E) Experimental outline: after 7 days of doxycycline-induced (Doxy) knockdown, mice were subjected to 10 Gy irradiation, and intestinal regeneration was assessed 4 days later. (F and G) Intestinal sections (F) analyzed by H&E and YAP IHC, and EdU (green) with DAPI (blue). Enlarged insets highlight Paneth cells (arrows) and quantification (G) of EdU+ crypts (n = 6 per group). Scale bars: 200 μm (overview) and 50 μm (enlarged insets). (H and J) Kaplan-Meier survival curves under constant (H) or intermittent (J) doxycycline administration for 4 weeks. Control group: shRen (n = 17 [H], n = 15 [J]); shY1 (n = 9); shT1, n = 11; shYT1 (n = 6 [H], n = 7 [J]); shYT2 (n = 6 [H], n = 4 [J]). (I) Representative H&E and PAS staining of liver, heart, and kidney sections from mice with the indicated genotypes after long-term depletion of YAP/TAZ. Scale bars: 200 μm. The liver H&E image panel for shYT 1 is also shown in Supplemental Figure 4 as a representative example. Data represent the mean ± SEM. Statistical analyses: 1-way ANOVA with Tukey’s HSD post hoc test (D and G) or ranked test (H).