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.