Short-course but not prolonged treatment with ATR inhibitor AZD6738 integrates with radiotherapy to generate a tumor antigen-specific CD8⁺ T cell expansion in the periphery

Abstract

ATR kinase is a central regulator of the DNA damage response. While ATR kinase inhibitors are known to sensitize cancer cells to DNA damage, their effect on immune cells is not known. Here we show in mice that short-course AZD6738 (ATRi) on days 1-3 decreases proliferating T cells in the tumor and periphery and that cessation of ATRi causes a proliferative rebound. Integrating radiation on days 1-2 (RT) with ATRi on days 1-3 increases IFN-beta in the tumor and activates tumor antigen-specific CD8+ T cells in the tumor-draining lymph node (DLN). RT with short-course ATRi induces an expansion of tumor antigen-specific CD8+ T cells in the DLN. In contrast, RT with prolonged daily ATRi blocks expansion of antigen-specific CD8+ T cells, despite increased IFN-beta and activation of CD8+ T cells. Our data identifies critical schedule considerations for ATRi with RT, immunotherapy and genotoxic therapies.