Nature of Sichuan University published an article on the development and verification of the whole process of clearance of mouse pancreatic tumors by a Pin1 inhibitor delivery system based on targeting CAFs

Recently, our institute and the research team of Karolinska Institutet in Sweden published a research paper in Nature Communications (IF=17.
694) in Nature Communications (IF=17.
694).
engagement
。 In this study, a prolyl isomerase PIN1 inhibitor delivery system based on CAFs-targeted antibodies and DNA barcode bundle gel system was developed, which introduced CD8+ T cells into tumors with CD8+ T cell-specific aptamers, achieved pancreatic tumor clearance in in an in situ model of mouse pancreatic cancer, and realized the treatment
of mouse pancreatic cancer by reshaping the tumor microenvironment.

Jiaye Liu, assistant researcher of Thyroid Surgery/Disease-related Molecular Network Frontier Science Center/Institute of Respiratory Health, Chunyang Mou, a master's student in liver surgery, Wang Jiao, a doctoral student at Karolinska Institutet, Sweden, is the first author of the paper, Professor Li Zhihui of Thyroid Surgery, Professor Wen Tianfu of Liver Surgery, Zheng Xiaofeng, researcher of Diabetes and Metabolism Research Center, and Associate Professor Liu Yong of Gastrointestinal Surgery are co-corresponding authors
of the paper.

CAFs are the main mesenchymal cell components in the tumor microenvironment, which can promote tumor growth
by maintaining the immunosuppressive tumor microenvironment and limiting the infiltration of immune cells through various mechanisms.
There is increasing evidence that prolyl isomerase PIN1 is overexpressed in cancer cells and CAFs cells of a variety of tumors, which can regulate the biological activity of their substrates, protein degradation or nucleus-cytoplasmic distribution, activate a variety of cancer-promoting signaling pathways, and have a key impact
on tumor genesis and progression.
Therefore, inhibition of prolyl isomerase Pin1 activity is considered a potential anti-cancer strategy, but none of the existing prolyl isomerase Pin1 inhibitors can effectively enter solid tumors
.

In this study, DNA barcode microcell systems (DMS), antifibroblast-DNA barcoding microcell systems (antiCAFs-DMS) and antifibroblast-DNA barcoding microcell systems-binding T cell aptamers (antiCAFs-AptT) were synthesized by self-assembly using PEG5K-cholesterol, DNA-barcoded cholesterol and prolyl isomerase PIN1 inhibitor AG17724.
Its structure and stability were characterized
.

Then, in vitro experiments confirmed that antiCAFs-DMS and antiCAFs-DMS-AptT could selectively deliver prolyl isomerase Pin1 inhibitor AG17724 to CAFs to achieve inhibition of CAFs without significant effect
on tumor cells.
At the same time, antiCAFs-DMS and antiCAFs-DMS-AptT can significantly reduce the expression of prolyl isomerase Pin1 downstream signaling molecules in CAFs
.

Next, the incubated antiCAFs-DMS-AptT and CD8+ T cells were introduced into the CAFs-tumor cell co-culture system, and antiCAFs-DMS-AptT was confirmed by immunofluorescence to promote the entry of CD8+ T cells into pancreatic
tumors.

Finally, antiCAFs-DMS-AptT was demonstrated in a mouse pancreatic cancer in situ tumor model by clearing CAFs in the tumor microenvironment and increasing the infiltration of CD8+ T cells
.

In summary, a prolyl isomerase PIN1 inhibitor delivery system based on CAFs-targeted antibodies and DNA barcode bundle gel system was developed
.
Based on CD8+ T cell-specific aptamers, the system can increase the infiltration of CD8+ T cells in the tumor microenvironment, and realize the treatment
of mouse pancreatic cancer by reshaping the tumor microenvironment.

Original link: https://doi.
org/10.
1038/s41467-022-31928-7