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

SIMPLE SUMMARY: Aspirin-triggered resolvin D1 (AT-RvD1) is biosynthesised by leukocytes as a mechanism to resolve inflammation during infection and/or injury. Emerging studies reveal that AT-RvD1 also has anti-cancer properties associated with stimulating macrophage-mediated clearance of tumour debris. No study to date has investigated how AT-RvD1 influences the neutrophil to lymphocyte ratio (NLR) in lung cancer, an established marker of poor prognosis. The biosynthesis of AT-RvD1 is dependent on the ALOX5 gene, and we reveal that ALOX5 mRNA expression was markedly reduced in lung adenocarcinoma tumours. We next utilised an oncogenic Kras(G12D) lung adenocarcinoma mouse model to investigate the efficacy of AT-RvD1 in vivo. We show for the first time that AT-RvD1 reduces tumour growth in the lungs of Kras(G12D) mice and alters the immune landscape in tumours by reducing the NLR. ABSTRACT: 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 (n = 48) and control tissue (n = 20) by IHC. Tumour expression of SAA and ALOX5 were analysed by RTqPCR and an oncogenic Kras(G12D) 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 KRAS mutation. AT-RvD1 treatment reduced tumour growth in Kras(G12D) 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 Kras(G12D) mice.