Obesity has been associated with poor clinical outcomes and chronic systemic inflammation in patients with breast cancer (BC). Metformin has demonstrated antitumorigenic effects both in pre-clinical and clinical studies. We hypothesize that chronic inflammation may lead to immune cell dysfunction in BC that can be restored via the use of metformin.
The effect of metformin on intratumoural (IT) immune cells was evaluated in two independent peri-surgical window studies (Dundee, n=29; Oxford, n=31) using immunohistochemistry for selected immune cell markers, pre- and post-metformin. Immune cell infiltrates were digitally quantified using Definiens Architect software and correlated to clinical parameters. Descriptive and linear regression techniques were applied using STATA software. Median densities and 95% confidence intervals were reported.
In the Dundee cohort, metformin was associated with a 2.5 (1.8-3.1) fold increase in IT CD68+ macrophages, 2.7 (2.1-9.8) fold increase in IT CD8+ T-cells and 0.5 (0.4-0.6) fold decrease in regulatory T-cells (Tregs) in patients with primary BC. These findings were validated in the Oxford cohort where metformin was significantly correlated with higher density of IT CD8+ T-cells and reduced Treg density (adj P<0.05). These changes were confined to the tumour islands rather than in the stroma. Stratified analysis by BMI in both cohorts showed an increase IT CD68+ macrophages and reduction in Tregs post metformin, in patients with high BMI (adj P<0.05) whereas there was no difference in patients with healthy BMI (adj P>0.05). In the Dundee cohort, linear regression showed that metformin was significantly associated with increased IT CD8+ independently of the baseline pathological or metabolic parameters [co-efficient 7.2, 95%CI (3.2-11.2)]. In the Oxford cohort, systemic inflammation (baseline serum leptin of >17 pg/ml) was associated with lack of correlation between CD8+ and PD1+ T-cells as well as between CD16+ and CD32B+ macrophages that was restored after the administration of metformin (adj P<0.05).
Metformin is associated with changes in the IT immune cells. Further work to understand potential combination with immunotherapy is required.
The authors.
Cancer Research UK Charity, Against Breast Cancer Charity and the European Society for Clinical Nutrition and Metabolism (ESPEN).
All authors have declared no conflicts of interest.