49P metformin is associated with increased intratumoural immune infiltrates in patients with primary invasive breast cancer

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: metformin is associated with changes in the IT immune cells. Further work to understand potential combination with immunotherapy is required.

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Identifiers

ORCID for C. Savva: orcid.org/0000-0003-0805-4719

ORCID for C. Birts: orcid.org/0000-0002-0368-8766

ORCID for S. Beers: orcid.org/0000-0002-3765-3342

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