Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy.

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.

• Authors: 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 Santagata, Gerburg M Wulf, Manuel Hidalgo, Senthil K Muthuswamy, Masafumi Nakamura, Nathanael S Gray, Xiao Zhen Zhou, Kun Ping Lu
• Journal: Cell (Cell) Vol. 184 Issue 18 Pg. 4753-4771.e27 (09 02 2021) ISSN: 1097-4172 [Electronic] United States
• PMID: 34388391 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• B7-H1 Antigen
• CD274 protein, human
• Equilibrative Nucleoside Transporter 1
• HIP1R protein, human
• Microfilament Proteins
• NIMA-Interacting Peptidylprolyl Isomerase
• SLC29A1 protein, human
• Deoxycytidine
• Pin1 protein, mouse
• Gemcitabine

Topics

• Adaptor Proteins, Signal Transducing (chemistry, metabolism)
• Adenocarcinoma (drug therapy, immunology, pathology)
• Allografts (immunology)
• Amino Acid Motifs
• Animals
• Apoptosis (drug effects)
• B7-H1 Antigen (metabolism)
• Cancer-Associated Fibroblasts (metabolism, pathology)
• Carcinoma, Pancreatic Ductal (drug therapy, immunology, pathology)
• Cell Line, Tumor
• Cell Membrane (drug effects, metabolism)
• Deoxycytidine (analogs & derivatives, pharmacology, therapeutic use)
• Drug Synergism
• Endocytosis (drug effects)
• Equilibrative Nucleoside Transporter 1 (metabolism)
• Humans
• Immunosuppression Therapy
• Immunotherapy
• Lysosomes (drug effects, metabolism)
• Mice
• Microfilament Proteins (chemistry, metabolism)
• Molecular Targeted Therapy
• NIMA-Interacting Peptidylprolyl Isomerase (metabolism)
• Oncogenes
• Organoids (drug effects, pathology)
• Pancreatic Neoplasms (drug therapy, immunology)
• Signal Transduction (drug effects)
• Survival Analysis
• Tumor Microenvironment (drug effects)
• Xenograft Model Antitumor Assays
• Gemcitabine