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Published on: January 17, 2025
Targeting PIN1 in Pancreatic Tumor Microenvironment with Peptide Amphiphiles Unleashes Immune Checkpoint Therapy
Yuanyuan Wu1,2,3,4, Jianan Guo1,2,3,4, Yuwei Zhang1,2,3,4
1Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Abstract:
Pancreatic cancer (PC) is a highly aggressive malignancy with a dismal 5-year survival rate of only 12%. Currently, no effective therapeutic strategies can improve the prognosis of pancreatic cancer. The activation of quiescent pancreatic stellate cells (PSCs) and their crosstalk with pancreatic cancer cells (PCCs) lead to the formation of a fibrotic physical barrier and an immunosuppressive tumor microenvironment (TME), which severely impede drug delivery and penetration. To improve PC treatment, a dual-targeting strategy capable of simultaneously acting on PCCs and PSCs is urgently needed to revert activated PSCs (aPSCs) to their quiescent state and suppress the proliferation of PCCs. KPT-6566, a small-molecule inhibitor, shifts PSCs from an activated to a quiescent state, reprograms the tumor immune microenvironment (TIME) to enhance anti-PD-L1 immunotherapy efficacy, suppresses PCCs proliferation, and induces PD-L1 expression on PCC surfaces, thereby increasing sensitivity to PD-L1-targeted therapies. This study designs two amphiphilic peptides, C16-LLGG-COO-DPPA-1(DPPA-1@PA) and DSPE-PEG-NHS-CGKRK(CGKRK@PA), which can co-assemble to encapsulate KPT-6566 and finally form a peptide-based nanoparticle termed DP-KPT-CG@PA. This nanoparticle precisely targets PCCs and PSCs to co-deliver KPT-6566, while synergizing with a PD-L1-blocking peptide to initiate immune checkpoint blockade therapy, thereby enhancing response rates to pancreatic cancer immunotherapy.
Insights
A novel nanoparticle delivers KPT-6566 to pancreatic cancer cells and pancreatic stellate cells, enhancing immunotherapy by reprogramming the tumor microenvironment and blocking PD-L1. This dual-targeting approach aims to improve pancreatic cancer treatment outcomes.
Area of Science:
- Oncology
- Nanotechnology
- Immunotherapy
Background:
- Pancreatic cancer (PC) has a poor prognosis due to its aggressive nature and limited therapeutic options.
- Activated pancreatic stellate cells (PSCs) and pancreatic cancer cells (PCCs) create a fibrotic barrier and immunosuppressive tumor microenvironment (TME), hindering treatment efficacy.
- A dual-targeting strategy is needed to simultaneously target PCCs and PSCs for improved PC treatment.
Purpose of the Study:
- To develop a peptide-based nanoparticle (DP-KPT-CG@PA) for co-delivery of KPT-6566 and a PD-L1-blocking peptide.
- To investigate the nanoparticle's ability to target PCCs and PSCs, revert activated PSCs (aPSCs) to quiescence, and suppress PCC proliferation.
- To evaluate the synergistic effect of the nanoparticle and PD-L1 blockade on enhancing pancreatic cancer immunotherapy.
Main Methods:
- Design and synthesis of two amphiphilic peptides: C16-LLGG-COO-DPPA-1 (DPPA-1@PA) and DSPE-PEG-NHS-CGKRK (CGKRK@PA).
- Co-assembly of peptides to encapsulate KPT-6566, forming the peptide-based nanoparticle DP-KPT-CG@PA.
- Evaluation of the nanoparticle's targeting capabilities, therapeutic effects on PCCs and PSCs, and immune reprogramming in the tumor immune microenvironment (TIME).
Main Results:
- The DP-KPT-CG@PA nanoparticle effectively co-delivers KPT-6566 to target PCCs and PSCs.
- KPT-6566 reprograms the TIME, enhancing anti-PD-L1 immunotherapy efficacy.
- The nanoparticle suppresses PCC proliferation and induces PD-L1 expression, increasing sensitivity to PD-L1-targeted therapies.
Conclusions:
- The developed peptide-based nanoparticle offers a promising dual-targeting strategy for pancreatic cancer.
- Co-delivery of KPT-6566 and PD-L1 blockade via DP-KPT-CG@PA enhances anti-tumor efficacy and immunotherapy response.
- This approach holds potential for improving treatment outcomes in pancreatic cancer patients.
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