Pancreatic tumor eradication via selective Pin1 inhibition in cancer-associated fibroblasts and T lymphocytes engagement

Cancer associated fibroblasts (CAFs) support tumors via multiple mechanisms, including maintaining the immunosuppressive tumor microenvironment and limiting infiltration of immune cells. The prolyl isomerase Pin1, whose overexpression in CAFs has not been fully profiled yet, plays critical roles in tumor initiation and progression. To decipher effects of selective Pin1 inhibition in CAFs on pancreatic cancer, here we formulate a DNA-barcoded micellular system (DMS) encapsulating the Pin1 inhibitor AG17724. DMS functionalized with CAF-targeting anti-FAP-α antibodies (antiCAFs-DMS) can selectively inhibit Pin1 in CAFs, leading to efficacious but transient tumor growth inhibition. We further integrate DNA aptamers (AptT), which can engage CD8+ T lymphocytes, to obtain a bispecific antiCAFs-DMS-AptT system. AntiCAFs-DMS-AptT inhibits tumor growth in subcutaneous and orthotopic pancreatic cancer models.


Reporting for specific materials, systems and methods
We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response. For the in vitro studies, no statistic method was used to predetermine sample size. We followed the conventional way of quantification accepted in our published paper (PMID: 35111955, 34650055) to determine the sample size. The minimum of three independent measurements were used allowing to perform statistical tests. For in vitro studies, We followed the previous experience maintaining the balance between the statistical significance and minimizing the number of used animals., and following already published papers in the context of cancer treatment (PMID: 35111955, 32327656).
No data was excluded from the study.
Biological replicates of each experiment in each panel were indicated in the figure legends, and all attempts at replication were successful.
For both in vivo and in vitro studies, allocation of samples and organisms into experimental groups was random.
The investigators were not blinded for the allocation of groups during experiments. Image analysis was conducted blinded, , because the researchers needed to keep track of the experiments and the analysis was performed by the same personnel. Fully blinded animal experiments were not possible due to personnel availability to accommodate such situations.
These cell lines are authenticated by the Sichuan University Characterized Cell Line Core Facility by STR profiling.
All cell lines were tested for and found to be free of mycoplasma contamination.
No commonly misidentified cell lines were used in the study. 6-8 week old female C57BL/6 mice were purchased from Chengdu Dashuo Biological Institute (Chengdu, China). All mice were maintained under ambient room temperature (22°C) with 40%-70% humidity and light/dark cycle of 12 hours/12 hours.
No wild animals were used in this study.
No field collected samples were used in this stud.
All animal experimental procedures were approved by the Animal Experimentation Ethics Committee of Sichuan University.