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

Marit Rasmussen; Karoline Alvik; Vinicius Kannen; Ninni E Olafsen; Linnea A M Erlingsson; Giulia Grimaldi; Akinori Takaoka; Denis M Grant; Jason Matthews

doi:10.3390/cancers15143689

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

Cancers (Basel). 2023 Jul 20;15(14):3689. doi: 10.3390/cancers15143689.

Authors

Marit Rasmussen¹, Karoline Alvik¹, Vinicius Kannen², Ninni E Olafsen¹, Linnea A M Erlingsson¹, Giulia Grimaldi³, Akinori Takaoka⁴, Denis M Grant², Jason Matthews^{1

2}

Affiliations

¹ Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway.
² Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
³ Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK.
⁴ Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, 7 Chome Kita 15 Jonishi, Sapporo 060-8628, Japan.

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.

Keywords: ADP-ribosylation; PARP7; breast cancer; tumor immunity; type I interferon.

Grants and funding

PTJ-162167/CAPMC/ CIHR/Canada