Article Alert: ATR Inhibition Enhances anti-PD-L1-based Immunotherapy Through Different Mechanisms

The kinase Ataxia telangiectasia and Rad3-related (ATR) regulates the DNA damage replication stress response (RSR) and promotes cell survival by preventing replication origin firing in the presence of compromised replication forks. Ceralasertib is a selective ATR inhibitor in clinical development that has demonstrated therapeutic promise for a number of malignancies in combination with the anti-PD-L1 agent durvalumab. However, the mechanism(s) that dictate the effects of ATR inhibition on immune cells and the tumor immune microenvironment (TIME) were undefined.

A novel study by Hardaker et al. contributes new insight into how ATR inhibition (i.e., ceralasertib) potentiates anti-PD-L1 therapy (1). Using mouse tumor models, the authors found that CD8+ T cells were required for the antitumor activity of ceralasertib and that intermittent dosing is required to allow T cell recovery. Ceralasertib also induced systemic changes in the immune cell milieu, including depletion of suppressive monocytic-MDSCs and tumor-associated macrophages (TAMs), an increase of activated dendritic cells, and enhanced PD-1 expression on T cells. In addition, the ATR inhibitor activated Type I interferon (IFNI) signaling in both tumor-bearing mice and cancer patients, which appears to mediate the antitumor action of a combined regimen with an anti-PD-L1 agent. In summary, Hardaker et al. have identified how ATR inhibition leads to activation of the immune response through cellular reprogramming and stimulation of IFNI-mediated signaling that impacts both normal and neoplastic components of the TIME.

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