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Reprogramming tumor-associated macrophages with lipid nanosystems reduces PDAC tumor burden and liver metastasis
Adrián Palencia-Campos1,2, Laura Ruiz-Cañas1,2,3, Marcelina Abal-Sanisidro4,5,6
1Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale CSIC-UAM, 28029, Madrid, Spain.
Background:
Pancreatic ductal adenocarcinoma (PDAC) requires innovative therapeutic strategies to counteract its progression and metastatic potential. Since the majority of patients are diagnosed with advanced metastatic disease, treatment strategies targeting not only the primary tumor but also metastatic lesions are needed. Tumor-Associated Macrophages (TAMs) have emerged as central players, significantly influencing PDAC progression and metastasis. Our objective was to validate an innovative therapeutic strategy involving the reprogramming of TAMs using lipid nanosystems to prevent the formation of a pro-metastatic microenvironment in the liver.
Results:
In vitro results demonstrate that M2-polarized macrophages lose their M2-phenotype following treatment with lipid nanoemulsions composed of vitamin E and sphingomyelin (VitE:SM), transitioning to an M0/M1 state. Specifically, VitE:SM nanoemulsion treatment decreased the expression of macrophage M2 markers such as Arg1 and Egr2, while M1 markers such as Cd86, Il-1b and Il-12b increased. Additionally, the TGF-βR1 inhibitor Galunisertib (LY2157299) was loaded into VitE:SM nanoemulsions and delivered to C57BL/6 mice orthotopically injected with KPC PDAC tumor cells. Treated mice showed diminished primary tumor growth and reduced TAM infiltration in the liver. Moreover, we observed a decrease in liver metastasis with the nanoemulsion treatment in an intrasplenic model of PDAC liver metastasis. Finally, we validated the translatability of our VitE:SM nanosystem therapy in a human cell-based 3D co-culture model in vivo, underscoring the pivotal role of macrophages in the nanosystem's therapeutic effect in the context of human PDAC metastasis.
Conclusions:
The demonstrated effectiveness and safety of our nanosystem therapy highlights a promising therapeutic approach for PDAC, showcasing its potential in reprogramming TAMs and mitigating the occurrence of liver metastasis.
Insights
This study shows a novel lipid nanosystem therapy effectively reprograms tumor-associated macrophages (TAMs) in pancreatic cancer (PDAC). This approach reduces primary tumor growth and liver metastasis, offering a promising new treatment strategy.
Area of Science:
- Oncology
- Nanomedicine
- Immunotherapy
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is aggressive with high metastatic potential.
- Tumor-associated macrophages (TAMs) are key drivers of PDAC progression and metastasis.
- Targeting TAMs offers a novel therapeutic strategy for advanced PDAC.
Purpose of the Study:
- To validate a lipid nanosystem for reprogramming TAMs.
- To assess the efficacy of this nanosystem in preventing liver metastasis in PDAC.
- To investigate the role of macrophages in the nanosystem's therapeutic effect.
Main Methods:
- In vitro studies with M2-polarized macrophages treated with Vitamin E and sphingomyelin (VitE:SM) nanoemulsions.
- In vivo studies using C57BL/6 mice with orthotopic KPC PDAC tumors and an intrasplenic liver metastasis model.
- Loading Galunisertib (TGF-βR1 inhibitor) into VitE:SM nanoemulsions for delivery.
- Validation in a human cell-based 3D co-culture model.
Main Results:
- VitE:SM nanoemulsions shifted M2 macrophages to M0/M1 states, decreasing M2 markers (Arg1, Egr2) and increasing M1 markers (Cd86, Il-1b, Il-12b).
- Nanoemulsion treatment reduced primary tumor growth and liver TAM infiltration in mice.
- Significant reduction in liver metastasis was observed in both orthotopic and intrasplenic models.
- Therapeutic effect was validated in a human PDAC co-culture model, confirming the role of macrophages.
Conclusions:
- The VitE:SM nanosystem effectively reprograms TAMs, inhibiting PDAC progression.
- This therapy demonstrates significant potential in preventing and reducing liver metastasis.
- The nanosystem represents a promising and safe therapeutic approach for PDAC.
