Tumor-associated Macrophages: re-education with Lipid Nanoparticles to avoid Liver Metastasis in PDAC

Dr. Bruno Sainz, Jr., Ph.D., Cancer Stem Cells and Fibroinflamatory Tumor Microenvironment Group, Ramon y Cajal University Hospital (IRYCIS), Madrid, Spain

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Date: 5.10.2022 at 14:00 (CET)

Tumor-associated Macrophages: re-education with Lipid Nanoparticles to reduce Liver Metastasis in PDAC

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers due in part to its metastatic nature. In PDAC, metastatic spread through the bloodstream results in metastasis in secondary organs, mainly to the liver, where immune cells, such as tumor-associated macrophages (TAMs) play a critical role. Indeed, recent studies have brought to the table the importance of TAMs not only in PDAC, but also in facilitating metastasis and in directing the evasion of the antitumor immune response.

Therefore, our aim is to reprogram TAMs from a pro-tumour state towards a pro-inflammatory (M0/1) phenotype with nanoparticles (NPs) composed of a battery of multiple bioactive lipids to avoid the formation of a tumorigenic microenvironment in the liver that favors PDAC metastasis. First, we evaluated in in vitro studies that re-education NP-based treatment of macrophages indeed promoted TAMs towards an M0/1 state. Specifically, NP treatment decreased the expression of M2 markers such as ARG1 or EGR2, and M1 markers such as CD86, IL1B or IL12B increased. Of all the formulations tested with different lipid compositions, NPs consisting of vitamin E and sphingomyelin were the most effective and least toxic.

Next, to check the effect of these NPs in vivo, we generated in vitro spheroids containing human pancreatic cancer cells PANC1, Cancer Associated Fibroblasts and primary monocyte-derived macrophages in order to recreate the tumour microenvironment in culture. We treated these spheroids with NPs and then implanted them orthotopically into the mouse pancreas. After two months, tumour growth and metastasis formation was evaluated by different techniques. By flow cytometry, we observed a reduction in the percentage of PANC1 GFP cells in the livers of mice implanted with treated spheroids. To validate this result we also performed qPCR analysis for human GAPDH expression, observing high amplification levels in control mice, confirming the presence of human cells in the liver and low amplification in mice receiving NP-treated spheroids.

With these results, we propose these NPs as an innovative therapy to re-educate TAMs to an M0/M1 state, with the intention of reducing liver metastasis in PDAC patients.