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

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 KrasG12D 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 KrasG12D 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 KrasG12D mice.

Gene Expression of the D-Series Resolvin Pathway Predicts Activation of Anti-Tumor Immunity and Clinical Outcomes in Head and Neck Cancer

“…Therefore, an impairment in the RvD pathway (biosynthesis and signaling) could be detrimental in cancer, since it is linked to poorer prognosis and associated with a transcriptomic landscape predictive of weak anti-tumor immunity. These findings are in agreement with previous results, demonstrating that RvD supplementation reduces cancer growth in experimental models of tumorigenesis [ 9 , 10 , 11 , 12 , 13 ].…”

“…We and others recently reported pre-clinical evidence that the stimulation of resolution is beneficial to counteract primary and metastatic neoplasia [ 9 , 10 , 11 , 12 , 13 ]. However, if and how resolution pathways are defective in cancer and influence tumorigenesis is still poorly understood.…”

NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase

“…This study found that AT-RvD1 inhibited the TGF-b1-induced epithelial to mesenchymal transition of A549 human lung adenocarcinoma epithelial cells, thus blocking tumor cell migration and metastasis [137]. In another model of lung adenocarcinoma in mice with an oncogenic Kras G12D mutation, AT-RvD1 decreased tumor growth and reduced the neutrophil-to-lymphocyte ratio, which is a marker for poor prognosis of cancer outcomes [138].…”

Tumor metabolic reprogramming in lung cancer progression (Review)

“…Various ω-3 metabolites of polyunsaturated fatty acids inhibit tumorigenic pathways; for example, the eicosapentaenoic acid metabolite ω-3,17,18-epoxide cascade activates anti-proliferation and pro-apoptosis pathways (85). Resolvins produced by LOX metabolites are effective inhibitors of tumor-derived inflammatory pathways (86). The cytosolic phospholipase A2-AA-COX-2 pathway is an important signaling pathway of inflammation, and some key factors of the pathway are associated with lung cancer.…”