Dihydroartemisinin remodels tumor micro-environment and improves cancer immunotherapy through inhibiting cyclin-dependent kinases

Abstract

Cancer immunotherapies are ineffective in nonresponding patients due to absence of immune responses. Here, we identified that dihydroartemisinin (DHA) induced immunogenic cell death (ICD) in hepatocellular carcinoma (HCC), proved by release or surface expose of damage-associated molecular patterns and in vivo protective vaccine activity. Mechanistically, DHA can inhibit cyclin-dependent kinases (CDKs), leading to a buildup of intracellular reactive oxygen species (ROS), which induces immunogenic cell death. In both Hepa1-6 and H22 tumor bearing mice, DHA exerted anti-tumor activity through increasing tumor-infiltrating CD8⁺ T cells with expression of activation makers (CD25 and CD69), secretion of intracellular cytokines (IFN-γ and TNF-α) and activated dendritic cells expressing MHCⅡ, CD80 and CD86. In hepa1-6 tumor bearing mice, DHA decreased immunosuppressive myeloid-derived suppressor cells. Furthermore, DHA enhanced the anti-PD-1 antibody and chimeric antigen receptor (CAR) T cell-mediated tumor suppression through recruitment and activation of endogenous CD8⁺ T cells. Overall, we demonstrated that by inhibiting CDKs, DHA can remodel tumor micro-environment to amplify anti-tumor immune responses in HCC. These findings provide a promising therapy option for HCC patients.

Keywords: Chimeric antigen receptor cell; Cyclin-dependent kinase; Dihydroartemisinin; Immunogenic cell death; Reactive oxygen species; Tumor micro-environment.