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 3

Tumor cell–specific YAP/TAZ depletion recapitulates ubiquitous YAP/TAZ depletion.

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Tumor cell–specific YAP/TAZ depletion recapitulates ubiquitous YAP/TAZ d...
(A) Acute depletion model: YAP/TAZ depletion was initiated at day 25 after HDTVI and analyzed at day 33 in the N-AKT CCA model. (B) IHC images of YAP staining (brown) in tumor-bearing livers. Arrows in the magnified view mark YAP+ tumor cells. Scale bars: 1 mm (overviews) and 50 μm (enlarged insets). (C and D) UMAP plots from scRNA-seq following acute YAP/TAZ depletion: (C) overview of cell types in the N-AKT CCA model; (D, left) cell composition in shRen and shYT tumors; (D, right) YAP activation scores indicated across all cell types, based on a conserved YAP signature (24) (shRen, n = 4; shYT 1, n = 2; shYT 2, n = 2). pDC, plasmacytoid DC. (E) Schematic of tissue-specific rtTA3 expression (Rosa26-CAG-lsl-RIK). Cre-mediated deletion of the STOP cassette enables tissue-specific shRNA expression in CAFs (Col1a2-Cre) or tumor cells (Cre via plasmid in HDTVI). (F and G) Kaplan-Meier survival curve (log-rank test) for mice with (F) CAF-specific (shRen, n = 13; shYT2, n = 14) or (G) tumor cell–specific (shRen, n = 10; shYT2, n = 13) YAP/TAZ knockdown.