Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy

Kazuhiro Koikawa, Shin Kibe, Futoshi Suizu, Nobufumi Sekino, Nami Kim, Theresa D. Manz, Benika J. Pinch, Dipikaa Akshinthala, Ana Verma, Giorgio Gaglia, Yutaka Nezu, Shizhong Ke, Chenxi Qiu, Kenoki Ohuchida, Yoshinao Oda, Tae Ho Lee, Babara Wegiel, John G. Clohessy, Nir London, Sandro SantagataGerburg M. Wulf, Manuel Hidalgo, Senthil K. Muthuswamy, Masafumi Nakamura, Nathanael S. Gray, Xiao Zhen Zhou, Kun Ping Lu

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4753-4771.e27
JournalCell
Volume184
Issue number18
DOIs
Publication statusPublished - Sep 2 2021

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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