OU-MRU Vol.9 Mar 2015

Okayama University Medical Research Updates （OU-MRU）

2015.03 Vol.9

Source: Okayama University, Center for Public Affairs and Communications
For immediate release: 23 March 2015
Okayama University research: Diabetes drug helps towards immunity against cancer(Okayama, 23 March) Studies reveal how a diabetes drug helps towards the rejection oftumours by supporting immune cells.

A 30-40% decrease in the risk of cancer has been observed in patients using the drug
metformin to treat diabetes 2. This characteristic is in striking contrast with insulin-based
diabetes treatments, which are linked to increases in cancer, however the mechanism
behind metformin’s anticancer effects has so far not been well understood. Now Heiichiro
Udono and colleagues at Okayama University and Kawasaki University in Japan explainthese anticancer responses in a report investigating the drug’s effects on the immune
system’s T cells.

The researchers tested the effects of dissolving metformin in the drinking water of mice
injected with leukaemia cells and confirmed complete rejection of the tumours. When themice were subsequently re-injected with twice the amount of cancer cells, no tumours
formed suggesting an immunologic memory response. Renal and skin cancers also
responded to the treatment and low doses similar to diabetes prescription concentrations
were still effective for tumour rejection. Further experiments with mice lacking certain cell
types showed that the influence of metformin on CD8+ T cells in particular was responsible
for the anticancer effects.

During chronic diseases including cancer, CD8+ T cells undergo a process called ‘immune
exhaustion’, where after repeated antigen (Ag) stimulation the cells can no longer secrete
chemicals crucial for the immune system to function. ‘Apoptosis’ or cell death of theseexhausted T cells ensues. The researchers incubated isolated T cells and found that CD8+ T
cells from metformin-treated mice still produced immune response chemicals.

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OU-MRU Vol.9 Mar 2015

Further comparisons revealed specific memory characteristics and protein producing
abilities in the T cells of metformin treated mice. “These findings provide novel insights into
anticancer immunity,” conclude the researchers in a report of their results. Further work isneeded to study the effects on different types of tumours and to clarify the specific cellularand molecular mechanisms involved.

Background
About metformin
Metformin is antihyperglycemic, and so counters insulin resistance. Early use has beenshown to increase survival in patients either suffering from obesity-involved type 2 diabetes
or cardiovascular disease or both.

The observed anticancer effects triggered further epidemiological studies that confirmed a30-40% reduction in cancer risk for patients treated with metformin. It was further shown toreduce cancer in a breast cancer mouse model and to increase life expectancy. However
while the mechanism seemed to stem from destruction of cancer initiating cells, until now
the mechanism was unclear.

Immune exhaustion
White blood cells in the immune system help protect the body against disease. T cells are aparticular type of white blood cell that fight infection by activating cells to release cytotoxic
cytokines – small proteins - and signalling chemicals instead of involving antibodies.

CD8+ are cytotoxic T cells that destroy virus cells and cancer tumours. However as cancer
cells and pathogens repeatedly stimulate CD8+, they eventually lose their ability to secrete
the signalling chemicals that cause cell death and regulate the immune system such as
interleukin 2 (IL-2), tumour necrosis factor alpha (TNFα) and interferon gamma (IFNγ). Thesechemicals continued to be produced by T cells isolated from metformin-treated mice.

In addition CD8+ cells in diseased organisms undergo phenotypic changes to express
exhaustion markers causing the cell death processes of apoptosis to ensue. Blocking thesemarkers has been studied as a means to tumour rejection and further studies are underway
to investigate T-cell exhaustion management in tumour immunotherapy.
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OU-MRU Vol.9 Mar 2015

Memory T cells
T cells that have encountered a disease or cancer can respond more quickly when facedwith the same pathogen a second time. This improved ‘memory response’ on second
encounter was observed in the metformin study.
Although these ‘memory T cells’ are not yet well understood, a classification model has
been proposed on the basis of acute viral studies. The model includes two types: centralmemory (TCMs) and effector memory (TEMs). The researchers studied the proportions ofTEMs and TCMs in tumour infiltrating white blood cells with and without metformin. They
found that TEM cells played a more significant role in tumour rejection.

Figure caption
Metformin improves the multifunctionality of antigen-specific CD8+ T cells in vivo. Miceinoculated with 2 × 105 melanoma cells were treated with or without metformin from day 7,
as indicated by the shadowed rectangle, and tumour growth was monitored. The results arerepresentative of two independent experiments. n = 5 per group.

Reference
Shingo Eikawa, Mikako Nishida, Shusaku Mizukami, Chihiro Yamazaki, Eiichi Nakayama, andHeiichiro Udono, Immune-mediated antitumor effect by type 2 diabetes drug, metformin,PNAS, 112(6), pp.1809-1814, 2015. DOI: 10.1073/pnas.1417636112
http://www.pnas.org/content/112/6/1809.abstract

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1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530 Japan© OKAYAMA University

OU-MRU Vol.9 Mar 2015

Correspondence toProfessor Heiichiro Udono, M.D., Ph.D.
Department of Immunology, Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences, Okayama University,
Shikata-cho 2-5-1, Okayama city, Okayama 700-8558, Japan
E-mail: udono@cc.okayama-u.ac.jp

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1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530 Japan© OKAYAMA University

OU-MRU Vol.9 Mar 2015

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About Okayama University
Okayama University is one of the largest
comprehensive universities in Japan withroots going back to the Medical Training
Place sponsored by the Lord of Okayama
and established in 1870. Now with 1,300
faculty and 14,000 students, the University
offers courses in specialties ranging frommedicine and pharmacy to humanities
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