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 Santagata; Gerburg M Wulf; Manuel Hidalgo; Senthil K Muthuswamy; Masafumi Nakamura; Nathanael S Gray; Xiao Zhen Zhou; Kun Ping Lu

doi:10.1016/j.cell.2021.07.020

Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy

Cell. 2021 Sep 2;184(18):4753-4771.e27. doi: 10.1016/j.cell.2021.07.020. Epub 2021 Aug 12.

Authors

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

Affiliations

¹ Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
² Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
⁴ Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁶ Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
⁷ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁸ Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁹ Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
¹⁰ Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
¹¹ Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
¹² Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
¹³ Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Division of Surgical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
¹⁴ Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
¹⁵ Department of Chemical and Structural Biology, The Weizmann Institute of Science, Rehovot, 7610001, Israel.
¹⁶ Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
¹⁷ Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: xzhouenator@gmail.com.
¹⁸ Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: klu@broadinstitute.org.

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.

Keywords: Pin1; cancer immune evasion; cancer-associated fibroblasts; chemotherapy; combination therapy; immuni checkpoint therapy; pancreatic cancer; targeted therapy; tumor immune microenvironment; tumor microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding