Immune-mediated antitumor effect by type 2 diabetes drug, metformin

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Metformin, a type 2 diabetes drug, exhibits potential anti-cancer properties.
• The precise immune-mediated mechanisms underlying metformin's anti-cancer effects remain largely unknown.

Purpose of the Study:

• To elucidate the immune-mediated mechanisms through which metformin exerts its anti-cancer effects.
• To investigate metformin's impact on CD8(+) tumor-infiltrating lymphocytes (TILs) and their anti-tumor functions.

Main Methods:

• Utilized T-cell-deficient SCID mice and normal mice to assess tumor rejection.
• Quantified CD8(+) TILs, apoptosis, and exhaustion markers (IL-2, TNFα, IFNγ).
• Investigated the role of AMP-activated protein kinase (AMPK) pathway and employed adoptive T-cell transfer.

Main Results:

• Metformin facilitated solid tumor rejection in normal mice but not in T-cell-deficient SCID mice.
• Metformin increased CD8(+) TILs, preserving their function and preventing exhaustion.
• A specific CD8(+) TIL subset (PD-1(-)Tim-3(+)) was identified as key for tumor rejection.
• Metformin treatment enhanced CD8(+) T cell migration and multifunctionality, dependent on AMPK signaling.

Conclusions:

• Metformin's anti-cancer activity is primarily immune-mediated, involving the enhancement of CD8(+) T cell responses.
• Metformin directly impacts CD8(+) T cells, protecting them from functional exhaustion in the tumor microenvironment.
• Targeting CD8(+) T cell responses with metformin represents a promising strategy for cancer immunotherapy.