Dopamine improves chemotherapeutic efficacy for pancreatic cancer by regulating macrophage-derived inflammations

Pancreatic cancer is an inflammatory malignancy, and tumor-associated macrophages (TAMs) are the predominant inflammatory cells in tumor tissue. TAMs have complicated interactions with pancreatic cancer cells, however, the details and mechanisms remain largely unknown. In this study, transcriptomics and proteomics analyses were performed to explore the interactions between murine pancreatic cancer cells and TAMs. Dopamine (DA) has been reported to suppress inflammations. However, its roles in TAMs of pancreatic cancer have not been reported. Herein, the roles and mechanisms of DA to affect the chemotherapeutic efficacy for pancreatic cancer were studied. Multi-omics results revealed that there was a tumor-promoting vicious cycle involving murine pancreatic cancer cells and TAMs. DA substantially improved the chemotherapeutic efficacy both in vitro study and in immunocompetent murine pancreatic cancer models by suppression of the M2 characters of TAMs. Further studies found that activation of DRD4 by DA led to the decrease of cAMP, and then inhibited the activation of PKA/p38 signal pathway, which suppressed the tumor-promoting inflammation of TAMs. This study uncovers the reciprocal interactions between TAMs and pancreatic cancer cells using multi-omics techniques and presents that DA has synergistic roles with chemotherapy for pancreatic cancer by suppressing of TAM-derived inflammations.