ATR inhibition: a new star in the sky of radioimmunotherapy! - PDF Version

As new radioimmunotherapies are introduced, the search for suitable inhibitors of the DNA damage response offers a promising new approach. Successful inhibition of DNA repair may enhance the effect of immunotherapy by activating the innate immune response, consequently leading to changes in the tumour microenvironment. Mechanisms that are involved in activation of the immune response by DNA damage include presentation of the neoantigen of the human leucocyte antigen (HLA) to T cell receptors; activation of the cytosolic DNA fragment-dependent cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING); and the signalling cascade known as ataxia-telangiectasia-mutated and Rad3-lated protein and checkpoint kinase 1 (ATM/ATR/Chk1). Therefore, it is suggested that the use of antibodies to the programmed death ligand 1 (anti-PD-1/PD-L1) with inhibitors of the ATM/ATR/Chk1 cascade may show high efficacy, especially in combination with radiotherapy.

After successful clinical implementation of poly-adenosine diphosphate ribose polymerase (PARP) inhibitors, these suggested mechanisms bring other DNA repair proteins into closer focus. Compared with PARP inhibitors, inhibition of the protein kinase ATR has the advantage that a whole spectrum of different DNA repair processes is deactivated, most of which serve to ensure error-free replication. Thus, it is not just a specific DNA-repair mechanism that is impaired, but the higher-level prevention of DNA damage (Sato et al., 2019; McLaughlin et al., 2020).

In this regard, Feng et al. (2020) have shown that ATR inhibition can significantly potentiate the innate immune response that is induced by ionising radiation. Using a series of mammalian knockout cell lines, the researchers observed that, surprisingly, both the cGAS/STING-dependent DNA-sensing pathway and the mitochondrial antiviral signalling (MAVS)-dependent RNA-sensing pathway were responsible for type-I interferon signalling that was induced by ionising radiation in the presence of ATR inhibitors. The relative contribution of these two pathways to type-I interferon signalling depends on the cell type and genetic background. In this case, the damage caused to DNA, either due to double-strand breaks or to replication stress, releases DNA fragments into the cytoplasm. This process may either activate the cGAS/STING-dependent signalling pathway, or, particularly in the case of AT-rich DNA sequences, be transcribed and initiate MAVS-dependent RNA sensing and signalling. Taken together, these results suggest the involvement of two distinct pathways of type-I interferon signalling after DNA damage. Hence, this observation offers a promising new starting point for a novel combination therapy that uses radiation plus ATR inhibition and that is particularly applicable to tumours with low mutational burdens.

Work by Vendetti et al. (2018), Dillon et al. (2019) and Sheng et al. (2020) supported this finding. They observed increased radiotherapy-induced stimulation of CD8+ T-cell infiltration and activation by inhibition of ATR in various xenograft models, which thereby reversed the immunosuppressive effect of radiation. Compared with radioimmunotherapy (radiotherapy plus anti-PD-L1), the addition of the ATR inhibitor increased T-cell infiltration and cell proliferation, enhanced the ability of tumour-infiltrating lymphocyte (TIL) CD8+ T cells to produce interferon- γ, and caused a decreasing trend in the number of TIL regulatory T cells. Thus, the immunological microenvironment of the tumour was significantly improved. As a result, triple therapy showed a greater advantage in antitumour efficacy and survival of mice than radioimmunotherapy alone. This illustrates further that the synergistic antitumour effect of ATR inhibition with radioimmunotherapy was due to activation of the cGAS/STING signalling that was caused by disruption of the DNA-repair pathways. Hence, several preclinical studies have shown that inhibition of ATR could be a potential synergistic treatment for radioimmunotherapy to control cell and tumour proliferation and to prolong survival. Whether these observations translate to patients should be the subject of future studies.

Sandra Classen, Felix Meyer and Kerstin Borgmann
Laboratory of Radiobiology & Experimental Radiooncology
Department of Radiotherapy and Radiation Oncology
Center of Oncology
University Hospital Hamburg-Eppendorf
Hamburg, Germany
borgmann@uke.de

Sandra Classen

Felix Meyer

Kerstin Borgmann