Possible Role of Metformin as an Immune Modulator in the Tumor Microenvironment of Ovarian Cancer.

Faye K Tsogas,Daniel Majerczyk,Peter C Hart

doi:10.3390/ijms22020867

Abstract

Growing evidence suggests that the immune component of the tumor microenvironment (TME) may be highly involved in the progression of high-grade serous ovarian cancer (HGSOC), as an immunosuppressive TME is associated with worse patient outcomes. Due to the poor prognosis of HGSOC, new therapeutic strategies targeting the TME may provide a potential path forward for preventing disease progression to improve patient survival. One such postulated approach is the repurposing of the type 2 diabetes medication, metformin, which has shown promise in reducing HGSOC tumor progression in retrospective epidemiological analyses and through numerous preclinical studies. Despite its potential utility in treating HGSOC, and that the immune TME is considered as a key factor in the disease’s progression, little data has definitively shown the ability of metformin to target this component of the TME. In this brief review, we provide a summary of the current understanding of the effects of metformin on leukocyte function in ovarian cancer and, coupled with data from other related disease states, posit the potential mechanisms by which the drug may enhance the anti-tumorigenic effects of immune cells to improve HGSOC patient survival.

Highlights

Most T lymphocyte subtypes failed to demonstrate an increase in survival rate, except for the intraepithelial CD8+ tumor-infiltrating lymphocytes (TILs). They found that a high intraepithelial CD8+ /CD4+ TIL ratio was associated with an improvement in the survival rate, whereas CD4+ TILs alone did not. These findings demonstrated the influence of CD8+ TILs on the prognosis for ovarian cancer (OvCa)
By expanding in vivo studies to assess circulating neutrophils and leukocytes and fully characterizing the distribution of various immune cells within the primary tumor and secondary sites, as well as determining the impact of metformin on neutrophil functions (i.e., NETosis) in the omental tumor microenvironment (TME), it will be possible to evaluate the effects of metformin on preventing a deleteriously pro-inflammatory microenvironment that promotes the metastasis of high-grade serous ovarian cancer (HGSOC)
While inflammatory responses to tumor growth display a number of mechanisms that are known to stimulate tumor cell self-renewal, proliferation, and motility [93], the ability to induce tumor cell lysis through enhancing T cell cytotoxic activity [61] or by introducing the adoptive transfer of functional T cells [94] clearly supports the idea that the immune system, and subsequent inflammatory signaling, can serve an anti-tumorigenic function

Summary

Introduction

In vivo xenograft studies have shown that clinically relevant doses of metformin given in a preventative regimen, including pretreatment prior to and maintenance during engraftment, have decreased the size of the primary tumor and inhibited the number of metastatic implants [18], suggesting that the physiological effects of the drug may involve its activity in the TME In line with these findings, recent studies have demonstrated that the drug could target mesothelial cells in a 3D organotypic model of invasion of the omentum, which was consistent with the decreased adhesion of HGSOC tumor cells to the omentum in explants removed from patients on metformin when compared to matched controls [19]. Potential for Immunoregulation by Metformin in the Ovarian Tumor Microenvironment

Metformin and T Cells—An Overview

Metformin enhances

Metformin and T Cells—Metabolic Targets and T Cell Phenotypes

Metformin and MDSCs—Clinical Implications and Limitations

Impact of Metabolism on Immune Cell Differentiation and Function

Conclusions