When cancer “met” its match: New study shows metformin-dependent antitumor immunity

OKAYAMA UNIVERSITY

IMAGE: SCIENTISTS REPORT THAT METFORMIN, USED TO TREAT TYPE 2 DIABETES MELLITUS, INDUCES ACTIVATION AND PROLIFERATION OF TUMOR-TARGETING CD8+ T-LYMPHOCYTES (CD8TIL), VIA MECHANISMS THAT INVOLVE THE GENERATION OF REACTIVE OXYGEN SPECIES IN MITOCHONDRIA OF CD8TIL AND AN INCREASE IN GLYCOLYSIS.

CREDIT: HEIICHIRO UDONO FROM OKAYAMA UNIVERSITY

Modern medicine has made slow progress in combating the menace of cancer. With all the permutations and combinations of cancer affecting millions of people worldwide, a blanket, yet targeted therapy would be ideal. Recently, certain drugs like metformin, which is used to treat lifestyle diseases like type 2 diabetes mellitus, have been found to have anti-cancer effects. Use of metformin appears to bolster anti-tumor immunity. However, the underlying immunological mechanisms have eluded scientists till date.

Japanese scientists led by Professor Heiichiro Udono from Okayama University thus decided to address this oncological research question. In their recent study, they looked at how a specific subset of immune cells, called CD8+ infiltrating T-lymphocytes (CD8TIL), which specifically attack tumor cells, behaved in response to metformin. Their findings have been published as a research article in Journal for ImmunoTherapy of Cancer.

Interestingly, Prof. Udono, who spearheaded the study, almost gave up on his anti-cancer pursuits, when he lost his own father to cancer. However, for him, inspiration came knocking at a conference, which he enthusiastically relates, “Nearly 10 years ago, a switch turned on in my head when I attended a Keystone Symposia discussing cancer, and hypoxia, held in Banff, Alberta. I realized that we had missed addressing Warburg effect, an effect which bolsters the growth of cancer, in our previous research. So, reverting Warburg effect to normal metabolic profile in cancers became a topic that got me thinking. Surprisingly, I got a hint from the same conference that metformin may aid cancer immunity. So, we got to work!”

Prof. Udono and his team meticulously executed a series of experiments on cancer cell lines, and mice genetically “knocked out” for possible biomolecules that result in metformin-dependent anti-tumor immunity. To arrive at their results, they probed the intracellular mechanisms in CD8TIL, when exposed to metformin, and assessed different biomarkers for growth. Given that CD8TIL produces proteins called interferons to attack cancer cells, they also assessed corresponding levels.

Accordingly, the scientists found that metformin causes the generation of reactive oxygen species in the mitochondria of CD8TIL (mtROS) and increases glycolysis. Further, they found that mtROS activated growth pathways in CD8TIL, thus allowing proliferation of these immune cells. Notably, this is achieved through a transcription factor involved in anti-oxidative stress  response, called Nrf. In addition, they also ruled out that metformin causes anti-tumor effect through ‘cell suicide’ or apoptosis. Also, they determined that metformin caused CD8TIL to robustly secrete interferon-ɣ to alter the tumor microenvironment to favor death of tumor cells.

Speaking about the findings, Prof. Udono exclaims, “More than anything else, our study provides the knowledge that we can ourselves protect our body from cancer. We hope that this understanding will result in not only the reduction of cancer incidence and improve treatment, but also will help prolong our life.”  The researchers also add that these findings strongly suggest the possibility of using metformin as a drug to strengthen anti-tumor immunity in patients with cancer.

This study bodes well for patients with cancer as well as cancer researchers worldwide.