An investigation of tumour-associated macrophages and statin therapy in human pulmonary adenocarcinoma

Introduction: Pulmonary adenocarcinoma represents a major area of unmet clinical need in cancer treatment. Recent advances in immunotherapy which target the PD-L1 immune checkpoint promise great improvements in outcomes for some patients. The immune system offers several other possible targets. Tumour associated macrophages (TAMs) are a common feature of lung tumour stroma. Epidemiological data have indicated a possible role of statins in reducing cancer mortality via their anti-inflammatory effects, but the mechanisms underpinning this are not clear. The possible roles of pro-tumour versus anti-tumour macrophages were investigated in lung adenocarcinomas, and the possibility of influencing this axis with statin drugs. Methods: Immunohistochemical evaluation was used with phenotyping of TAMs using multiplex immunohistochemistry in tissue microarray sections of about 300 lung adenocarcinomas with matched clinicopathological data. Quantitative digital pathology, using Hamamatsu scanner images and Visiopharm software to count and phenotype TAMs in TMA sections. Results: It has been found that the pro-tumourigenic (CD68+CD163+) TAM numbers are elevated in invasive versus in situ tumour regions. Interestingly, statin users have significantly lower protumourigenic macrophage numbers than non-statin users, significantly in areas of in situ tumour growth in comparison to invasive lesions. Tumours in statin users were also of significantly lower histological grade, showing a higher percentage of in situ components than non-statin users. Conclusion: Automated image analysis methods efficiently count and classify macrophages in tumour tissue. Statin therapy is related to macrophage class, specifically within in situ lesions. These data support a model whereby statins target protumourigenic TAMs in early disease, highlighting their potential as cancer-preventive agents.