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Oral Metformin and Polymetformin Reprogram Immunosuppressive Microenvironment and Boost Immune Checkpoint Inhibitor Therapy in Colorectal Cancer
Author(s) -
Xiong Yang,
Song Wantong,
Shen Limei,
Wang Ying,
Zhang Jing,
Hu Mengying,
Liu Yun,
Li Jingjing,
Musetti Sara,
Liu Rihe,
Huang Leaf
Publication year - 2020
Publication title -
advanced therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2366-3987
DOI - 10.1002/adtp.202000168
Subject(s) - tumor microenvironment , immune checkpoint , cancer research , immune system , colorectal cancer , immunotherapy , medicine , blockade , cancer , metformin , cancer immunotherapy , immunology , receptor , insulin
Immune checkpoint inhibitors (ICI), especially PD‐1/PD‐L1 inhibitors, are emerging as promising therapeutic options for patients with advanced tumors, but the response rate in the majority of colorectal cancer (CRC) patients remains low. Herein, the use of metformin (Met) and its polymeric form (Polymet) to enhance the response rate of immune checkpoint blockade therapy is reported. Oral Met and Polymet significantly enhance the antitumor effect of ICI therapy in a murine orthotopic CRC model. Further analyses reveal that Met and Polymet reprogram the immunosuppressive tumor microenvironment via activation of adenosine 5′‐monophosphate‐activated protein kinase and inhibition of the mammalian target of rapamycin signaling pathway, stimulating T cell infiltration into the tumor. Additionally, oral Met and Polymet change the abundance of key microbes in the intestinal environment, including increasing the Lactobacillus population, which should exert tumor‐suppressing activities in the CRC. These findings highlight the potential of combining Met or Polymet with cancer immunotherapy and provide a strategy for sensitizing CRC patients to immune checkpoint blockade therapy.