Statin use is associated with lower pro-tumourigenic (M2) macrophage number in the microenvironment of in situ versus invasive lung adenocarcinoma


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Esraa Aldujaily1,Tamihiro Kamata2,David Moore3,Catrin Pritchard4,John LeQuesne5
1University of Leicester,2Department of Molecular Cell Biology, University of Leicester, UK,3Department of Cancer Studies, University of Leicester, UK,4Department of Cancer Studies, University of Leicester, UK; Department of Molecular Cell Biology, University of Leicester, UK,5MRC Toxicology Unit, Leicester, UK

Abstract

Background

Non-small cell lung cancer (NSCLC) is the commonest cause of cancer death globally and represents a major area of unmet clinical need. Adenocarcinoma is the most common subtype of NSCLC. Epidemiological data have indicated a possible role of statins in reducing cancer mortality,but the mechanisms underpinning this are not clear. We have investigated this further in lung adenocarcinoma and have focused on assessing the effect of statins on protumourigenic M2 tumour associated macrophage (TAM) numbers in in situ versus invasive disease because of previous data in other system suggestive of anti-inflammatory properties of statins.

Method

  1. Immunohistochemical evaluation and phenotyping of TAMs using CD68 and CD163 markers in tissue microarray (TMA) sections.
  1. Digital pathology, using Hamamatsu scanner and Visiopharm software to count and phenotype TAMs in TMA sections.

Results

We analysed 165 lung adenocarcinoma cases (406 x 1mm cores) in three TMA sections. We found that the M2 (CD68+CD163+) positive TAM numbers were significantly higher in invasive tumour regions than in situ areas in both statin and non-statin users. However, interestingly, statin users had significantly lower M2 macrophage numbers than non-statin users, but only in regions of in situ tumour growth. Overall  statin users also had significantly lower histological grade cancers than non-users and contained a higher percentage of in situ components than non-statin users. 

Conclusion

Digital pathology and region-specific TMAs provide an accurate, new automated assay to count, phenotype and study the anatomical distribution of TAMs in human lung adenocarcinoma.

We present for the first time a comprehensive study of the anatomical distribution of TAMs by phenotype in lung adenocarcinoma within three compartments; tumour, stroma and lumina. Our data show that statin therapy is related to macrophage number specifically within in situ lesions. These data support a model whereby statins target M2 protumourigenic TAMs in early disease, highlighting their potential as cancer-preventive agents.