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セコム科学技術振興財団

研究成果報告書

研究課題名

メトホルミンによる腫瘍局所免疫疲弊解除に基づく癌免疫治療
Cancer Immunotherapy by metformin-induced reversion of exhausted T cells in tumor
microenvironment

研究期間
平成 26 年 4 月 ～ 平成 30 年 3 月

報告年月
平成 30 年 6 月
研究代表者
岡山大学 大学院医歯薬学総合研究科 免疫学分野 教授
鵜殿 平一郎Department of Immunology, Okayama University Graduate School of Medicine, Dentistry andPharmaceutical Sciences
Heiichiro Udono

Abstract
Recent advances in immunotherapy have changed the landscape of cancer therapy. Immune checkpoint
inhibitors have shown improved patient survival rates over traditional chemotherapy.
Tumor-infiltrating CD8 T lymphocytes often undergo loss of function, referred to as immune
exhaustion, which facilitates tumor growth in vivo. Immune checkpoint inhibitors prevent thisinhibition of effector CD8 T cells, resulting in their reactivation and subsequent inhibitionof tumor growth. However, this treatment is effective in less than 20% of patients with non-small
cell lung carcinoma, as well as other cancers. It remains unknown why the remaining 80% patientswith cancer do not respond to the same inhibitors. Although combination therapy with different
checkpoint inhibitors has demonstrated greater success rates than monotherapy, its very high costcreates financial challenges. To overcome these problems, low molecular weight compounds having
similar effects as checkpoint inhibitors are currently being explored. Metformin, a drug commonlyprescribed for the treatment of type 2 diabetes (T2DM), is a potential candidate for this purpose.
Metformin is currently prescribed as a first-line therapy for T2DM because of its
glucose-lowering effects, as well as its safety and low cost. T2DM patients receiving metformin
have a lower incidence of cancer and mortality compared with those receiving other anti-diabetes
drugs, though the reasons for this remain unclear. Direct inhibition of cancer and the reductionof insulin and insulin-like growth factors have been proposed as the reason for the observed cancer
prevention effect. Conversely, we found that metformin induced the reversal of immune exhaustionin tumor-infiltrating CD8 T cells, resulting in tumor regression in mice tumor models. Thesesurprising findings are now being confirmed by other studies worldwide.
Recent studies revealed that the function of immune cell subsets is tightly coupled to theirenergy metabolism. Effector T cells and M1-like macrophages depend on glycolysis to exert theirfunctions, whereas immune-suppressive cells involved in wound healing and tolerance depend onoxidative phosphorylation (OxPhos) following fatty acid oxidation (FAO). In the tumor
microenvironment, Treg, MDSCs, and M2-like macrophages undergo expansion, while effector andmemory CD8 T cells and M1-like macrophages are very rare. This suggests that the immune cells
that undergo expansion in tumors are dependent on OxPhos following FAO, whereas tumor cells uptake
most of the glucose and are dependent on glycolysis (Warburg effect). Metformin appears to improvethe metabolic imbalance in the tumor-infiltrating cells, but not in peripheral blood lymphocytes.
Metformin-induced metabolic reprogramming causes CD8 T cells to increase the Glut1 expression(hence, elevate their levels of glycolysis), resulting in greater anti-tumor activity.
Metformin-mediated complex I inhibition induces the production of ROS. ROS then activate Nrf2,
which in turn activates mTORC1, resulting in cell proliferation.
Metformin acts synergistically with anti-PD-1 Ab blockade through the overlap of certain signal
cascades. It is possible that artificial manipulation of the metabolism of tumor-infiltrating
immune cells improves immune tolerance against tumors. In fact, metformin activates glycolysis,
leading to the inhibition of Treg and MDSCs in tumors. Based on this evidence, we have begun anintervention trial for patients with cancer using Nivolumab and metformin. The knowledge that
immune cell function is closely associated with cellular metabolism may offer additional
possibilities in the advancement of cancer immunotherapy.