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

Abstract

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 response is dependent on glucose growth conditions and metabolic phenotype in colorectal cancer cells

“…As an orally ingested drug, its highest concentration is found in the gastrointestinal (GI) tract, and GI derived tumours would most likely be affected 28 , which further indicates that achieved drug concentration play a major role in tumour responses. This is recapitulated in its various mode of action ranging from influence on microbiota 29 , immune modulation 30 , and direct intracellular effect 31 .…”

Inactivation of AMPK Leads to Attenuation of Antigen Presentation and Immune Evasion in Lung Adenocarcinoma

“…The widely used antidiabetic drug metformin can reprogram the tumor microenvironment in lung cancer (12), esophageal squamous cell carcinoma (13) and colorectal cancer (14). As metformin also activates the LKB1 substrate AMPK (15), we hypothesized that inactivation of AMPK may contribute to the suppressive TIME in LKB1 deficient tumors.…”

The Effect of Type 2 Diabetes Mellitus on the Short-Term Outcomes and Prognosis of Stage I–III Colorectal Cancer: A Propensity Score Matching Analysis

“…Metformin enhanced response to radiotherapy and chemotherapy through synergistic interactions, indicating that it might help induce tumor regression. 25,26 PSM analysis is a statistical technique, which can deal with confounding bias and mimic a randomized clinical trial, improving the level of evidence in studies. 27 As far as we know, there were no related PSM studies about T2DM and CRC, and this is the first study to analyze the potential effect of T2DM on CRC using PSM.…”