Apoptotic pancreatic cancer cells induce apoptosis in mesenchymal stromal cells


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Ester Pfeifer1,Debashis Sarker1,Joy Burchell1,Francesco Dazzi1
1King's College London

Abstract

Background

Treatment resistance in pancreatic ductal adenocarcinoma (PDAC) is attributed to the heterogenous tumour microenvironment (TME), characterized by a desmoplastic stroma and dysfunctional immune cells. Apoptosis of cancer cells can be successfully induced in vitro. However, when put into context of the microenvironment, apoptosis might have undesired effects both via the apoptosis of the cancer cells and when affecting the surrounding cells. We have recently shown that mesenchymal stromal cells (MSCs) undergoing apoptosis can directly and indirectly suppress T-cell activity. We therefore hypothesized that MSCs will undergo apoptosis when interacting with PDAC cells exposed to an apoptotic stimuli and hence have an immunosuppressive effect on the TME.

Method

The PDAC cell lines BxPc-3, SW-1990, MiaPaca-2, PANC-1 and CFPAC-1 were treated with TNF-related apoptosis inducing ligand (TRAIL). Apoptosis was evaluated by with Annexin V and 7 AAD staining and subsequently analysed by flowcytometry. MSCs were co-cultured with TRAIL treated or untreated PDAC cells. Supernatant from TRAIL treated/untreated PDAC cells was collected after 24 hours and added to MSCs and incubated for 24h.

Results

BxPc-3, MiaPaca-2 and SW 1990 were sensitive to TRAIL. MSCs in co-culture with TRAIL treated BxPc-3 cells underwent apoptosis compared to MSCs co-cultured with untreated BxPc-3 cells. MSCs also underwent apoptosis when subjected to the supernatant from TRAIL treated BxPc-3, MiaPaca-2 and SW 1990 cells, suggesting that it is a secreted factor from the apoptotic PDAC cells influencing MSCs to undergo apoptosis. Preliminary results suggest that the effect is fibroblast specific. 

Conclusion

Knowing that apoptotic MSCs are driving macrophages and T-cells to an immunosuppressive phenotype, our findings suggests that using apoptosis inducing drugs in cancer patients might contribute to a more immunosuppressive TME via MSC apoptosis. Currently, work is ongoing to explore the effect of apoptotic PDAC cells on other fibroblasts and TME cellular components.