Loss of PARP7 Increases Type I Interferon Signaling in EO771 Breast Cancer Cells and Prevents Mammary Tumor Growth by Increasing Antitumor Immunity

SIMPLE SUMMARY: Cancer development depends on interactions between the tumor microenvironment and the immune system. PARP7 negatively regulates the type I interferon pathway, ultimately preventing immune cells from detecting and eliminating cancer cells. Recently, inhibition of PARP7 activity has been shown to restore type I interferon signaling, resulting in tumor regression. Here we investigated the effect of stable PARP7 knockout in mammary cancer cells and used a genetic mouse model to study the effects of PARP7 loss on tumor growth in vivo. ABSTRACT: PARP7 is a member of the ADP-ribosyltransferase diphtheria toxin-like (ARTD) family and acts as a repressor of type I interferon (IFN) signaling. PARP7 inhibition causes tumor regression by enhancing antitumor immunity, which is dependent on the stimulator of interferon genes (STING) pathway, TANK-binding kinase 1 (TBK1) activity, and cytotoxic CD8(+) T cells. To better understand PARP7′s role in cancer, we generated and characterized PARP7 knockout (Parp7(KO)) EO771 mouse mammary cancer cells in vitro and in a preclinical syngeneic tumor model using catalytic mutant Parp7(H532A) mice. Loss of PARP7 expression or inhibition of its activity increased type I IFN signaling, as well as the levels of interferon-stimulated gene factor 3 (ISGF3) and specifically unphosphorylated-ISGF3 regulated target genes. This was partly because PARP7′s modification of the RelA subunit of nuclear factor κ-B (NF-κB). PARP7 loss had no effect on tumor growth in immunodeficient mice. In contrast, injection of wildtype cells into Parp7(H532A) mice resulted in smaller tumors compared with cells injected into Parp7(+/+) mice. Parp7(H532A) mice injected with Parp7(KO) cells failed to develop tumors and those that developed regressed. Our data highlight the importance of PARP7 in the immune cells and further support targeting PARP7 for anticancer therapy.