Aspirin-Triggered Resolvin D1 Reduces Proliferation and the Neutrophil to Lymphocyte Ratio in a Mutant KRAS-Driven Lung Adenocarcinoma Model

• Main Authors: Amanda Vannitamby, Mohamed I. Saad, Christian Aloe, Hao Wang, Beena Kumar, Ross Vlahos, Stavros Selemidis, Louis Irving, Daniel Steinfort, Brendan J. Jenkins, Steven Bozinovski
• Format: Article
• Language: English
• Published: MDPI AG 2021-06-01
• Series: Cancers
• Subjects: lung cancer; adenocarcinoma; neutrophils; resolution; inflammation; ALOX5
• Online Access: https://www.mdpi.com/2072-6694/13/13/3224

Tumour-associated neutrophils (TANs) can support tumour growth by suppressing cytotoxic lymphocytes. AT-RvD1 is an eicosanoid that can antagonise neutrophil trafficking instigated by ALX/FPR2 ligands such as serum amyloid A (SAA). We aimed to establish whether SAA and ALOX5 expression associates with TANs and investigate the immunomodulatory actions of AT-RvD1 in vivo. MPO-positive neutrophils were quantified in tumour blocks from lung adenocarcinoma (<i>n</i> = 48) and control tissue (<i>n</i> = 20) by IHC. Tumour expression of SAA and ALOX5 were analysed by RTqPCR and an oncogenic <i>Kras^G12D</i> lung adenocarcinoma mouse model was used to investigate the in vivo efficacy of AT-RvD1 treatment. ALOX5 expression was markedly reduced in lung adenocarcinoma tumours. The SAA/ALOX5 ratio strongly correlated with TANs and was significantly increased in tumours harbouring an oncogenic <i>KRAS</i> mutation. AT-RvD1 treatment reduced tumour growth in <i>Kras^G12D</i> mice, which was accompanied by suppressed cellular proliferation within parenchymal lesions. In addition, AT-RvD1 significantly reduced the neutrophil to lymphocyte ratio (NLR), an established prognostic marker of poor survival in adenocarcinoma. This study identifies a novel molecular signature whereby elevated levels of SAA relative to ALOX5 favour accumulation of TANs. Furthermore, the ALOX5/5-LO enzymatic product, AT-RvD1, markedly reduced the NLR and suppressed tumour growth in <i>Kras^G12D</i> mice.