Metformin generates profound alterations in systemic and tumor immunity with associated antitumor effects

Abstract

BackgroundMetformin is a commonly used antidiabetic medication which has demonstrated promise as an anticancer agent alone and in combination with conventional treatment regimens. There is increasing evidence that metformin can also generate immunomodulatory effects in solid tumors and is currently being investigated as an adjunct to immune checkpoint inhibitors (ICIs). We hypothesized that metformin would generate a shift in immunity unfavorable to tumor growth and tested this hypothesis in a preclinical model of head and neck cancer.MethodsUsing a syngeneic mouse model of human papillomavirus-associated head and neck cancer (mEER/MTEC), we tested the impact of metformin on systemic and local immunity and tumor growth velocity. We compared the effects of acute and chronic treatment regimens on immunocyte presence and activation using a combination of flow cytometry and targeted transcriptomic analysis.ResultsAcute metformin exposure generated measurable shifts in systemic myeloid and T-cell populations in non-tumor-bearing mice and decreased myeloid derived suppressor cell (MDSC) levels in tumor draining lymph nodes of tumor-bearing mice. Although metformin decreased regulatory T-cell (T-reg) and MDSC levels and increased CD8+ levels in murine tumors when combined with ICIs, acute metformin exposure was insufficient to generate substantial antitumor activity. Conversely, long-term metformin treatment significantly reduced tumor growth velocity, increased the CD8+/T-reg ratio, increased tumor infiltrating lymphocyte levels and upregulated component genes of the previously validated T-cell inflamed expression profile.ConclusionsMetformin generates complex systemic and local immune effects which vary as a function of treatment duration. Combinatorial strategies with ICIs must take into account both the complexity and variability of these effects in order to generate maximal antitumor activity in future clinical trials.

Metformin inhibits melanoma cell metastasis by suppressing the miR-5100/SPINK5/STAT3 axis

“…We suspect metformin pretreatment not only impacts intracellular pathways to inhibit metastasis, but also modulates the extracellular microenvironment, e.g., adhesion molecules [ 48 ], vascular leakiness [ 49 ], and extracellular matrix remodeling [ 49 ] in distant organs. Of note, metformin also led to the activation of antitumor immune and metabolic reprogramming in both lab experiments and clinical trials [ 50 – 53 ]. Thus, metformin pretreatment reinforced these effects and showed fewer metastasis foci.…”

Metformin and Cancer, an Ambiguanidous Relationship

“…Metformin administration induces interferon-gamma (IFN-γ) production in CD8+ tumor infiltrating lymphocytes in multiple solid tumor models [ 145 , 146 , 147 ]. Furthermore, metformin inhibited accumulation and suppressive activity of myeloid-derived suppressor cells, which are a major immunosuppressive cell type that inhibits T-cells and promotes tumor immune escape [ 145 , 148 ]. Interestingly, metformin is detrimental to CD19-chimeric antigen receptor-modified T cells as it inhibits proliferation and cytotoxicity while inducing apoptosis via AMPK activation and downstream suppression of mTOR [ 149 ].…”

Metabolic Implications of Immune Checkpoint Proteins in Cancer

“…The antitumor and immune effects of metformin are complex. Dosing and scheduling can have profound effects, and the challenges lie in determining optimal treatment regimens [ 158 ]. Furthermore, the impact of metformin on immune checkpoint protein expression should be further elucidated as studies have shown that metformin inhibits PD-L1 by endoplasmic reticulum-associated protein degradation in breast cancer cells [ 154 ].…”