Metformin changes the immune microenvironment of colorectal cancer in patients with type 2 diabetes mellitus

Accumulating evidence suggests that metformin reduces the incidence and mortality of colorectal cancer (CRC). However, underlying mechanisms have not been fully clarified. The aim of this study was to examine the pathological characteristics of resected CRC from patients treated with metformin for t...

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Bibliographic Details
Published in:Cancer science Vol. 111; no. 11; pp. 4012 - 4020
Main Authors: Saito, Akira, Kitayama, Joji, Horie, Hisanaga, Koinuma, Koji, Ohzawa, Hideyuki, Yamaguchi, Hironori, Kawahira, Hiroshi, Mimura, Toshiki, Lefor, Alan Kawarai, Sata, Naohiro
Format: Journal Article
Language:English
Published: England John Wiley & Sons, Inc 01.11.2020
John Wiley and Sons Inc
Subjects:
Adult
Aged
Aged, 80 and over
Antibodies
CD163 antigen
CD3 antigen
CD8 antigen
Cloning
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - complications
Colorectal Neoplasms - immunology
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - pathology
Diabetes
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Type 2 - complications
Diabetes Mellitus, Type 2 - immunology
Diabetes Mellitus, Type 2 - metabolism
Female
Fibrosis
Gender
Hemoglobin
Humans
Hypoglycemic Agents - pharmacology
Immunohistochemistry
Insulin
Invasiveness
Lymphocytes
Lymphocytes, Tumor-Infiltrating - immunology
Lymphocytes, Tumor-Infiltrating - metabolism
Lymphocytes, Tumor-Infiltrating - pathology
Macrophages
Male
Metastasis
Metformin
Metformin - pharmacology
Middle Aged
Mortality
Neoplasm Metastasis
Neoplasm Staging
Original
Phenotypes
Regression analysis
Stroma
Surgery
tertiary lymphoid structure
Tumor Microenvironment - drug effects
Tumor Microenvironment - immunology
Tumor-Associated Macrophages - drug effects
Tumor-Associated Macrophages - immunology
Tumor-Associated Macrophages - metabolism
Tumors
tumor‐associated macrophage
tumor‐infiltrating lymphocytes
Denmark
tertiary lymphoid structure
metformin
tumor-associated macrophage
tumor-infiltrating lymphocytes
colorectal cancer
ISSN:1347-9032, 1349-7006, 1349-7006
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Summary:Accumulating evidence suggests that metformin reduces the incidence and mortality of colorectal cancer (CRC). However, underlying mechanisms have not been fully clarified. The aim of this study was to examine the pathological characteristics of resected CRC from patients treated with metformin for type 2 diabetes mellitus (DM). In total, 267 patients with DM underwent curative colectomy for Stage I‐III CRC and 53 (19.9%) patients had been treated medically including metformin. Pathological N‐stage was significantly lower in metformin‐treated patients (P < .05) with prolonged disease‐free survival (DFS) (P < .05). Immunohistochemistry showed that the densities of CD3(+) and CD8(+) tumor‐infiltrating lymphocytes (TILs) in the invasive front area were significantly higher in 40 patients treated with metformin compared with propensity score matched cases without metformin (P < .05). The density of tertiary lymphoid structures (TLS) in tumor stroma was markedly increased in metformin‐treated patients (P < .001). In those tumors, there were more CD68(+) tumor‐associated macrophages (TAM) infiltrated (P < .05), while the ratio of CD163(+) M2‐phenotype was markedly reduced (P < .001). Stromal fibrosis tended to be suppressed by metformin intake (P = .051). These findings suggested that metformin drastically changes the characteristics of infiltrating immune cells in CRC and reprograms the tumor microenvironment from immunosuppressive to immunocompetent status, which may lead to suppression of microscopic tumor spread and improve the outcomes of patients with CRC and type 2 DM. Metformin treatment is associated with fewer lymphatic metastases with prolonged disease‐free survival in patients with stage I‐III colorectal cancer and diabetes mellitus. Densities of tumor‐infiltrating CD3(+) and CD8(+) T cells and tertiary lymphoid structures are significantly increased, while the ratio of CD163(+) M2 type tumor‐associated macrophages is decreased in metformin‐treated colorectal tumor. Metformin may suppress tumor spread by changing the immunosuppressive tumor microenvironment to an immunocompetent status.
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ISSN:1347-9032
1349-7006
1349-7006
DOI:10.1111/cas.14615