Rasmussen Marit, Alvik Karoline, Kannen Vinicius, Olafsen Ninni E, Erlingsson Linnea A M, Grimaldi Giulia, Takaoka Akinori, Grant Denis M, Matthews Jason
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway.
Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Cancers (Basel). 2023 Jul 20;15(14):3689. doi: 10.3390/cancers15143689.
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) EO771 mouse mammary cancer cells in vitro and in a preclinical syngeneic tumor model using catalytic mutant 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 mice resulted in smaller tumors compared with cells injected into mice. mice injected with Parp7 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.
PARP7是ADP核糖基转移酶白喉毒素样（ARTD）家族的成员，作为I型干扰素（IFN）信号通路的抑制剂。PARP7抑制通过增强抗肿瘤免疫力导致肿瘤消退，这依赖于干扰素基因刺激因子（STING）通路、TANK结合激酶1（TBK1）活性和细胞毒性CD8 T细胞。为了更好地理解PARP7在癌症中的作用，我们在体外以及使用催化突变小鼠的临床前同基因肿瘤模型中，生成并鉴定了PARP7基因敲除（Parp7）的EO771小鼠乳腺癌细胞。PARP7表达缺失或其活性受到抑制会增加I型IFN信号通路，以及干扰素刺激基因因子3（ISGF3）的水平，特别是未磷酸化的ISGF3调控的靶基因。这部分是因为PARP7对核因子κB（NF-κB）的RelA亚基进行了修饰。PARP7缺失对免疫缺陷小鼠的肿瘤生长没有影响。相比之下，与注射到野生型小鼠体内的细胞相比，将野生型细胞注射到Parp7小鼠体内会导致肿瘤更小。注射Parp7细胞的小鼠未能形成肿瘤，而那些已形成肿瘤的小鼠肿瘤则消退了。我们的数据突出了PARP7在免疫细胞中的重要性，并进一步支持将PARP7作为抗癌治疗的靶点。
