Wee1 kinase inhibitor AZD1775 potentiates CD8+ T cell-dependent antitumour activity via dendritic cell activation following a single high dose of irradiation

As standard treatments for cancer, DNA-damaging chemotherapeutic agents and irradiation therapy improve survival in patients with various cancers. Wee1, a kinase associated with the cell cycle, causes G2/M cell cycle arrest to allow repair of injured DNA in cancer cells, and a Wee1 inhibitor has been confirmed to lead to apoptosis in cancer cells. Recently, there has been renewed interest in exploring the immune environment which plays a significant role in tumour suppression. A Wee1 inhibitor combined with radiotherapy has been tested in lung, pancreatic, and prostate cancer and melanoma in vivo or in vitro. There is still no research evaluating the immunoregulatory effects of AZD1775 plus high-dose irradiation (IR) in vivo. T cell killing and CD8+ T cell depletion assays demonstrated that the combination of AZD1775 and IR delayed tumour growth in breast cancer mouse models. Additionally, combination treatment also suppressed the expression of PD-L1, a co-inhibitor, through the STAT3-IRF1 axis. The importance and originality of this study are that it explores the internal and external mechanisms of AZD1775 combined with a single high dose of IR and provides a rationale for applying the combination therapy described above in a clinical trial.