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Updated: Oct 24, 2025
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy
Kazuhiro Koikawa1, Shin Kibe2, Futoshi Suizu3
1Division 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.
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.
Insights
Pin1 inhibition overcomes pancreatic cancer resistance by targeting tumor microenvironment and key cancer cell pathways. This approach synergizes with immunotherapy and chemotherapy for effective pancreatic ductal adenocarcinoma treatment.
Area of Science:
- Oncology
- Cancer Immunology
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits significant resistance to therapies due to tumor heterogeneity and a suppressive tumor microenvironment (TME).
- The role of proline isomerase Pin1 in PDAC's TME and its potential in cancer immunotherapy remain largely unexplored.
Purpose of the Study:
- To investigate the role of Pin1 in PDAC progression and its impact on the tumor microenvironment.
- To evaluate the therapeutic potential of Pin1 inhibition in combination with existing treatments for PDAC.
Main Methods:
- Analysis of Pin1 expression in PDAC patient samples and correlation with survival.
- In vitro and in vivo studies using clinically available Pin1 inhibitors combined with anti-PD-1 therapy and gemcitabine.
- Mechanistic studies to elucidate Pin1's role in cancer-associated fibroblasts (CAFs), PD-L1, and ENT1 regulation.
Main Results:
- Pin1 is overexpressed in PDAC cells and CAFs, correlating with poorer patient survival.
- Pin1 inhibition, in combination with anti-PD-1 and gemcitabine, led to complete tumor elimination or sustained remission in preclinical models.
- Pin1 inhibition disrupts the desmoplastic and immunosuppressive TME, upregulates PD-L1 and gemcitabine transporter ENT1, and inhibits multiple cancer pathways.
Conclusions:
- Pin1 is a critical driver of PDAC's aggressive phenotype and therapeutic resistance.
- Targeting Pin1 offers a promising strategy to overcome PDAC resistance by modulating the TME and enhancing immunochemotherapy efficacy.
- Pin1 inhibition renders PDAC susceptible to eradication by combined immunochemotherapy.
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