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

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 (Parp7KO) EO771 mouse mammary cancer cells in vitro and in a preclinical syngeneic tumor model using catalytic mutant Parp7H532A 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 Parp7H532A mice resulted in smaller tumors compared with cells injected into Parp7+/+ mice. Parp7H532A mice injected with Parp7KO 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.

Design, Synthesis, and Structure–Activity Relationship of Novel Pyridazinone-Based PARP7/HDACs Dual Inhibitors for Elucidating the Relationship between Antitumor Immunity and HDACs Inhibition

“…The mixture was quenched with cool water (150 mL) at room temperature and extracted with EtOAc (100 mL × 3). The combined organic layers were washed brine (20 General Procedure for the Preparation of 9g−9h. Methyl 6-(4-Iodo-1H-pyrazol-1-yl)hexanoate (32a).…”

“…18,19 Recently, PARP7 was confirmed to involve in cytosolic NA sensing and multiple viral RNA infections through repressing IFN-I signaling. 2,20 Mechanistically, when viral infection takes place, PARP7 inhibits the autophosphorylation of TBK1 by MARylate TBK1, which is essential for the activation of TBK1 and type I interferon response and anticancer immunity. 21,22 Some studies have shown that inhibitors of PARP7 induce IFN-I signaling in mouse colorectal cancer (CT-26) cells and human lung adenocarcinoma (NCI-H1373) cells in an immune cell-dependent manner, which leads to tumor cell death in vivo.…”

“…Poly­[adenosine diphosphate (ADP)-ribose] polymerases (PARPs) are members of a family of 17 enzymes that catalyze the covalent transfer of a single ADP-ribose (i.e., mono­(ADP-ribose) or MAR in abbreviation) or multiple ADP-ribose ( i.e. , poly­(ADP-ribose) or PAR) from nicotinamide adenine dinucleotide (NAD + ) onto their substrates. , Among them, one member of the monoPARP subfamily, PARP7 (also known as TiPARP), has been reported to MARylate itself and other substrate proteins. , PARP7 was originally identified as a gene that strongly upregulated by ligands (e.g., the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD] and chemical l -Kynurenine) of aryl hydrocarbon receptor (AHR) and PARP7MARylate AHR to negatively regulate the transcriptional activity of AHR. , Recently, PARP7 was confirmed to involve in cytosolic NA sensing and multiple viral RNA infections through repressing IFN-I signaling. , Mechanistically, when viral infection takes place, PARP7 inhibits the autophosphorylation of TBK1 by MARylate TBK1, which is essential for the activation of TBK1 and type I interferon response and anticancer immunity. , Some studies have shown that inhibitors of PARP7 induce IFN-I signaling in mouse colorectal cancer (CT-26) cells and human lung adenocarcinoma (NCI-H1373) cells in an immune cell-dependent manner, which leads to tumor cell death in vivo. ,, Atamparib (RBN-2397, depicted in Figure ) represents an orally bioavailable compound with selective inhibition against PARP7, which is currently undergoing phase 2 clinical trials.…”

Unraveling the inhibitory potential of Rosetta designed de novo cyclic peptides on PARP7 through molecular dynamics simulations

“…12 The evidence from mouse experiments further supports the potential of utilizing PARP7 inhibitors as targeted agents for cancer therapy. 23 PARP12, a member of the PARP family, is also a monoPARP that plays a crucial role in regulating cell survival and regulating cell regeneration. 24 Notably, emerging evidence suggests that targeting PARP12 holds promise as a novel approach to alleviate the resistance of breast cancer cells to genotoxic stress.…”

Novel Bifunctional Conjugates Targeting PD-L1/PARP7 as Dual Immunotherapy for Potential Cancer Treatment

“…PARP7 (TIPARP) was originally identified as a gene that is strongly upregulated by ligands of aryl hydrocarbon receptor (AHR) and PARP7 MARylate AHR to negatively regulate the transcriptional activity of AHR . Recently, studies have shown that inhibition of PARP7 could restore type I interferon (IFN) signaling responses and might activate the immune system to prevent tumor escape. , RBN-2397 ( 1 , Figure ), an oral PARP7 inhibitor (PARP7i) developed by Ribon Therapeutics Inc., is the first PARP7 inhibitor to enter clinical study. It is currently being investigated in combination with anti-PD-1 antibody pembrolizumab for squamous cell carcinoma of the lung (SCCL) .…”