Reduced Protumorigenic Tumor-Associated Macrophages with Statin Use in Premalignant Human Lung Adenocarcinoma

Abstract

Background: Statins have anticancer properties by acting as competitive inhibitors of the mevalonate pathway. They also have anti-inflammatory activity, but their role in suppressing inflammation in a cancer context has not been investigated to date. Methods: We have analyzed the relationship between statin use and tumor-Associated macrophages (TAMs) in a cohort of 262 surgically resected primary human lung adenocarcinomas. TAMs were evaluated by multiplex immunostaining for the CD68 pan-TAM marker and the CD163 protumorigenic TAM marker followed by digital slide scanning and partially automated quantitation. Links between statin use and tumor stage, virulence, and cancer-specific survival were also investigated in a wider cohort of 958 lung adenocarcinoma cases. All statistical tests were two-sided. Results: We found a statin dose-dependent reduction in protumorigenic TAMs (CD68 CD163 ) in both stromal (P .021) and parenchymal (P .003) compartments within regions of in situ tumor growth, but this association was lost in invasive regions. No statistically significant relationship between statin use and tumor stage was observed, but there was a statin dose-dependent shift towards lower histological grade as assessed by growth pattern (P .028). However, statin use was a predictor of slightly worse cancer-specific survival (P .032), even after accounting for prognostic variables in a multivariable Cox proportional hazards survival model (hazard ratio 1.38, 95% confidence interval 1.04 to 1.84). Conclusions: Statin use is associated with reduced numbers of protumorigenic TAMs within preinvasive lung adenocarcinoma and is related to reduced tumor invasiveness, suggesting a chemo-preventive effect in early tumor development. However, invasive disease is resistant to these effects, and no beneficial relationship between statin use and patient outcome is observed.