Shifting the Soil: Metformin Treatment Decreases the Protumorigenic Tumor Microenvironment in Epithelial Ovarian Cancer

Simple Summary Metformin is a drug commonly used to treat diabetes but it may play a role in cancer treatment. It is not known exactly how metformin acts on cancer cells and cells in the tumor microenvironment (TME). Our previous work suggested that metformin may be altering specific cells in the tumor microenvironment called cancer-associated mesenchymal stem cells (CA-MSC). The aim of this study was to build on our previous work to understand the impact of metformin on the TME. We demonstrated that when individuals with epithelial ovarian cancer received metformin in addition to chemotherapy, their tumors were less likely to have CA-MSC and T regulatory cells, which are both known to promote tumor growth, when compared to tumors from individuals who received chemotherapy alone. Additional experiments with ovarian cancer cells and tumors grown in mice suggested that metformin might be best used to prevent tumor growth rather than treat advanced stage disease. Controversy persists regarding metformin's role in cancer therapy. Our recent work suggested metformin acts by impacting the tumor microenvironment (TME), normalizing the epigenetic profile of cancer-associated mesenchymal stem cells (CA-MSC). As CA-MSC can negatively impact tumor immune infiltrates, we evaluated metformin's impact on the human TME, focusing on the interplay of stroma and immune infiltrates. Tumor samples from (i) 38 patients treated with metformin and chemotherapy and (ii) 44 non-metformin matched controls were included in a tissue microarray (TMA). The TMA was used to compare the presence of CA-MSC, desmoplasia and immune infiltrates in the TME. In vitro and in vivo models examined metformin's role in alteration of the CA-MSC phenotype. The average percentage of CA-MSC was significantly lower in metformin-treated than in chemotherapy alone-treated tumors (p = 0.006). There were fewer regulatory T-cells in metformin-treated tumors (p = 0.043). Consistent with CA-MSC's role in excluding T-cells from tumor islets, the T-cells were primarily present within the tumor stroma. Evaluation of metformin's impact in vitro suggested that metformin cannot reverse a CA-MSC phenotype; however, the in vivo model where metformin was introduced prior to the establishment of the CA-MSC phenotype supported that metformin can partially prevent the reprogramming of normal MSC into CA-MSC. Metformin treatment led to a decrease in both the presence of protumorigenic CA-MSC and in immune exclusion of T cells, leading to a more immune-permissive environment. This suggests clinical utility in prevention and in treatment for early-stage disease and putatively in immune therapy.