Kannen Vinicius, Rasmussen Marit, Das Siddhartha, Giuliana Paolo, Izzati Fauzia N, Choksi Hani, Erlingsson Linnea A M, Olafsen Ninni E, Åhrling Samaneh S, Cappello Paola, Teino Indrek, Maimets Toivo, Jaudzems Kristaps, Gulbinas Antanas, Dambrauskas Zilvinas, Edgar Landon J, Grant Denis M, Matthews Jason
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
Front Immunol. 2025 Jan 10;15:1513595. doi: 10.3389/fimmu.2024.1513595. eCollection 2024.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, and despite low incidence rates, it remains the sixth leading cause of cancer related deaths worldwide. Immunotherapy, which aims to enhance the immune system's ability to recognize and eliminate cancer cells, has emerged as a promising approach in the battle against PDAC. PARP7, a mono-ADP-ribosyltransferase, is a negative regulator of the type I interferon (IFN-I) pathway and has been reported to reduce anti-tumour immunity.
We used murine pancreatic cancer cells, CR705, CRISPR/Cas9, in vivo tumour models and spectral flow cytometry to determine the role of PARP7 in pancreatic tumour growth.
Loss of Parp7 elevated the levels of interferon stimulated gene factor 3 (ISGF3) and its downstream target genes, even in the absence of STING. Cancer cells knocked out for Parp7 (CR705Parp7KO) produced smaller tumours than control cells (CR705Cas9) when injected into immunocompetent mice. Transcriptomic analyses revealed that CR705Parp7KO tumours had increased expression of genes involved in immunoregulatory interactions and interferon signalling pathways. Characterization of tumour infiltrating leukocyte (TIL) populations showed that CR705Parp7KO tumours had higher proportions of natural killer cells, CD8+ T cells and a lower proportion of anti-inflammatory macrophages (M2). The overall TIL profile of CR705Parp7KO tumours was suggestive of a less suppressive microenvironment.
Our data show that loss of Parp7 reduces PDAC tumour growth by increasing the infiltration of immune cells and enhancing anti-tumour immunity. These findings provide support to pursue PARP7 as a therapeutic target for cancer treatment.
胰腺导管腺癌（PDAC）是最致命的癌症形式之一，尽管发病率较低，但它仍是全球癌症相关死亡的第六大主要原因。免疫疗法旨在增强免疫系统识别和消除癌细胞的能力，已成为对抗PDAC的一种有前景的方法。PARP7是一种单ADP-核糖基转移酶，是I型干扰素（IFN-I）途径的负调节因子，据报道它会降低抗肿瘤免疫力。
我们使用小鼠胰腺癌细胞CR705、CRISPR/Cas9、体内肿瘤模型和光谱流式细胞术来确定PARP7在胰腺肿瘤生长中的作用。
即使在没有STING的情况下，Parp7的缺失也会提高干扰素刺激基因因子3（ISGF3）及其下游靶基因的水平。当注射到具有免疫活性的小鼠体内时，敲除Parp7的癌细胞（CR705Parp7KO）产生的肿瘤比对照细胞（CR705Cas9）小。转录组分析显示，CR705Parp7KO肿瘤中参与免疫调节相互作用和干扰素信号通路的基因表达增加。肿瘤浸润白细胞（TIL）群体的特征表明，CR705Parp7KO肿瘤中自然杀伤细胞、CD8 + T细胞的比例较高，抗炎巨噬细胞（M2）的比例较低。CR705Parp7KO肿瘤的总体TIL谱表明其微环境的抑制性较小。
我们的数据表明，Parp7的缺失通过增加免疫细胞浸润和增强抗肿瘤免疫力来减少PDAC肿瘤生长。这些发现为将PARP7作为癌症治疗的治疗靶点提供了支持。
