Dendritic Cells(Radboud University Medical Center)

There is a lack of a well-established approach for assessment of early treatment outcomes for modern therapies for pancreatic ductal adenocarcinoma (PDAC) e.g. dinaciclib or dendritic cell (DC) vaccination. Here, we developed multivariate models using MRI texture features to detect treatment effects following dinaciclib drug or DC vaccine therapy in a transgenic mouse model of PDAC including 21 LSL-Kras^G12D ; LSL-Trp53^R172H ; Pdx-1-Cre (KPC) mice used as untreated control subjects (n=8) or treated with dinaciclib (n=7) or DC vaccine (n=6). Support vector machines (SVM) technique was performed to build a linear classifier with three variables for detection of tumor tissue changes following drug or vaccine treatments. Besides, multivariate regression models were generated with five variables to predict survival behavior and histopathological tumor markers (Fibrosis, CK19, and Ki67). The diagnostic performance was evaluated using accuracy, area under the receiver operating characteristic curve (AUC) and decision curve analyses. The regression models were evaluated with adjusted r-squared (R_adj ²). SVM classifier successfully distinguished changes in tumor tissue with an accuracy of 95.24% and AUC of 0.93. The multivariate models generated with five variables were strongly associated with histopathological tumor markers, fibrosis (R_adj ²=0.82, P<0.001), CK19 (R_adj ²=0.92, P<0.001) and Ki67 (R_adj ²=0.97, P<0.001). Furthermore, the multivariate regression model successfully predicted survival of KPC mice by interpreting tumor characteristics from MRI data (R_adj ²=0.91, P<0.001). The results demonstrated that MRI texture features had great potential to generate diagnosis and prognosis models for monitoring early treatment response following dinaciclib drug or DC vaccine treatment and also predicting histopathological tumor markers and long-term clinical outcomes.

Antitumor effects and mechanism of combined therapy with a dendritic cell (DC) vaccine and fluorouracil (5-FU) were investigated. Cytotoxic activity against MC38 cells, untreated or pretreated with 5-FU, was examined in splenocytes from mice inoculated with DCs: DCs pulsed with MC38 lysate or treated with LPS or both and untreated DCs. Inoculation with all types of DCs induced the significant cytotoxic activity of splenocytes, and pretreatment of MC38 cells with 5-FU significantly enhanced the cytotoxic activity of splenocytes. Depletion of natural killer (NK) cells, but not of CD8 or CD4 T cells, in the splenocytes from DC (without MC38 lysate-pulse or LPS treatment thereafter)-inoculated mice decreased the cytotoxic activity. The cytotoxic effect was eliminated by treatment with a monoclonal antibody (mAb) against tumor necrosis factor (TNF)-alpha and was partially inhibited by concanamycin A. Inoculation of mice with DCs upregulated TNFalpha expression on NK cells. MC38 cells pretreated with 5-FU exhibited enhanced expression of procaspase 8 and efficiently underwent apoptosis by TNF-alpha with activation of caspase 8. Although treatment with 5-FU upregulated Rae-1 expression on MC38 cells, the NK-cell-mediated cytotoxic activity was not suppressed by treatment with an anti-Rae-1 mAb or an antinatural killer group 2D mAb or both. These results indicate that combined therapy with a DC vaccine and 5-FU is a promising strategy for cancer treatment mediated by the tumoricidal activity of NK cells through the TNF-alpha pathway.