Co-treatment of ticagrelor and anti-PD-1 immunotherapy in tumor-associated macrophages reduces pancreatic cancer cell growth and migration through the TGF-β1/Smad2 pathway.

Pancreatic ductal adenocarcinoma (PDAC) is the third primary cause of cancer-related mortality in the US. PDAC is associated with an immunosuppressive tumor microenvironment (TME) that restricts the effectiveness of immunotherapies. Immunosuppressive tumor-associated macrophages (TAMs), the most abundant cell type in TME, express immune checkpoint ligands, including programmed cell death protein 1 (PD-1) ligand 1 (PD-L1). Targeting PD-1/PD-L1 alone has no effect in PDAC, highlighting the need for combination approaches. P2Y12, an ADP receptor, is expressed by macrophages, and P2Y12 antagonists promote phagocytosis, in turn, is linked to anti-tumor activity. Here, we tested the combined blockade of PD-1/PD-L1 and P2Y12 on TAMs in pancreatic cancer. For this purpose, we set up co-cultures of pancreatic cancer cells and TAMs and treated them with inhibitor BMS-1, which blocks PD-1/PD-L1 interaction, cemiplimab to block PD-1, and ticagrelor to block P2Y12. We observed that the co-treatment of ticagrelor and cemiplimab promoted TAM phagocytic ability and inhibited the TAM-induced growth and migration of cancer cells. The combination of ticagrelor and cemiplimab inhibited TGF-β1 release from TAMs and Smad2 phosphorylation in cancer cells. Our data suggest that co-treatment of ticagrelor and cemiplimab in TAMs inhibits pancreatic cancer cell growth and migration by suppressing the TGF-β1/Smad2 signaling pathway, providing an emerging strategy aimed at re-educating or depleting TAMs to enhance the efficacy of immunotherapy in pancreatic cancer.