Circulating tumour cells as an indicator of early and systemic recurrence after surgical resection in pancreatic ductal adenocarcinoma.

Early recurrence in pancreatic ductal adenocarcinoma (PDAC) is a decisive factor in determining a patient's prognosis. We determined in our current study whether circulating tumour cells (CTCs) exist in the blood of PDAC patients and can be used as a predictor of recurrence patterns (i.e. time and site) after surgical resection. Between December 2017 and November 2018, the mononuclear cell layer was obtained from the peripheral blood of 36 patients diagnosed with PDAC. CTCs were then isolated using the CD-PRIME™ platform and detected via immunostaining. The patient records were analyzed to correlate these data with survival and recurrence patterns. Twelve patients were CTC-positive (33.3%) and showed a significantly frequent rate of systemic recurrence (distant metastases and peritoneal dissemination) (p = 0.025). On multi-variable logistic regression analysis, CTC positivity was an independent risk factor for early recurrence (p = 0.027) and for systemic recurrence (p = 0.033). In summary, the presence or absence of CTC in the blood of the patients with PDAC could help predict the recurrence pattern after surgery. PDAC patients with CTC positivity at tumour diagnosis should therefore undergo a comprehensive strategy for systemic therapy and active monitoring to detect possible early recurrence.

Diversity in the Extracellular Vesicle-Derived Microbiome of Tissues According to Tumor Progression in Pancreatic Cancer.

This study was conducted to identify the composition and diversity of the microbiome in tissues of pancreatic cancer and to determine its role. First, extracellular vesicles (EVs) were obtained from the paired tumor and normal tissues, and 16s rRNA gene sequencing was performed. We identified the microbiomes, compared the diversity between groups, and found that Tepidimonas was more abundant in tumors. Second, larger tumors resulted in lower levels of Leuconostoc and Sutterella, and increased lymph node metastasis resulted in higher levels of Comamonas and Turicibacter in tumor tissues. Moreover, in the case of tumor recurrence, the levels of Streptococcus and Akkermansia were decreased in tumor tissues. Finally, with the supernatant of Tepidimonasfonticaldi, proliferation and migration of cells increased, and epithelial-mesenchymal transition and the Tricarboxylic Acid (TCA) cycle-related metabolites were enhanced. The composition and diversity of EV-derived microbiomes are important for providing novel insights into theragnostic approaches in pancreatic cancer.

Rationally designed redirection of natural killer cells anchoring a cytotoxic ligand for pancreatic cancer treatment.

The emergence of T-cell engineering with chimeric antigen receptors (CARs) has led to attractive therapeutics; however, autologous CAR-T cells are associated with poor clinical outcomes in solid tumors because of low safety and efficacy. Therefore, the aim of our study was to develop a CAR therapy with enhanced cytotoxicity against solid cancer using allogeneic NK cells. In this study, we engineered "off-the-shelf" NK cells to redirect them towards pancreatic ductal adenocarcinoma (PDAC) by improving their target-specific cytotoxic potential. By integrated bioinformatic and clinicopathological analyses, folate receptor alpha (FRα) and death receptor 4 (DR4) were significantly highly expressed in patient-derived tumor cells. The combined expression of FRα and DR4/5 was associated with inferior clinical outcomes, therefore indicating their use as potential targets for biomolecular treatment. Thus, FRα and DR4 expression pattern can be a strong prognostic factor as promising therapeutic targets for the treatment of PDAC. For effective PDAC treatment, allogeneic CAR-NK cells were reprogrammed to carry an apoptosis-inducing ligand and to redirect them towards FRα and initiate DR4/5-mediated cancer-selective cell death in FRα- and DR4/5-positive tumors. As a result, the redirected cytotoxic ligand-loaded NK cells led to a significantly enhanced tumor-selective apoptosis. Accordingly, use of allogeneic CAR-NK cells that respond to FRα and DR4/5 double-positive cancers might improve clinical outcomes based on personal genome profiles. Thus, therapeutic modalities based on allogeneic NK cells can potentially be used to treat large numbers of patients with optimally selective cytotoxicity.