| Literature DB >> 34388391 |
Kazuhiro Koikawa1, Shin Kibe2, Futoshi Suizu3, Nobufumi Sekino4, Nami Kim5, Theresa D Manz6, Benika J Pinch6, Dipikaa Akshinthala7, Ana Verma8, Giorgio Gaglia8, Yutaka Nezu9, Shizhong Ke4, Chenxi Qiu4, Kenoki Ohuchida10, Yoshinao Oda11, Tae Ho Lee12, Babara Wegiel13, John G Clohessy14, Nir London15, Sandro Santagata8, Gerburg M Wulf7, Manuel Hidalgo7, Senthil K Muthuswamy7, Masafumi Nakamura10, Nathanael S Gray16, Xiao Zhen Zhou17, Kun Ping Lu18.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance to current therapies attributed to inherent tumor heterogeneity and highly desmoplastic and immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1 regulates multiple cancer pathways, but its role in the TME and cancer immunotherapy is unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associated fibroblasts (CAFs) and correlates with poor survival in PDAC patients. Targeting Pin1 using clinically available drugs induces complete elimination or sustained remissions of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine in diverse model systems. Mechanistically, Pin1 drives the desmoplastic and immunosuppressive TME by acting on CAFs and induces lysosomal degradation of the PD-1 ligand PD-L1 and the gemcitabine transporter ENT1 in cancer cells, besides activating multiple cancer pathways. Thus, Pin1 inhibition simultaneously blocks multiple cancer pathways, disrupts the desmoplastic and immunosuppressive TME, and upregulates PD-L1 and ENT1, rendering PDAC eradicable by immunochemotherapy.Entities:
Keywords: Pin1; cancer immune evasion; cancer-associated fibroblasts; chemotherapy; combination therapy; immuni checkpoint therapy; pancreatic cancer; targeted therapy; tumor immune microenvironment; tumor microenvironment
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Year: 2021 PMID： 34388391 PMCID： PMC8557351 DOI： 10.1016/j.cell.2021.07.020
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 66.850