Abstract
Simple SummaryImmunotherapy improved the therapeutic landscape for patients with advanced cancer diseases. However, many patients do not benefit from immunotherapy. The bidirectional crosstalk between myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) contributes to immune evasion, limiting the success of immunotherapy by checkpoint inhibitors. This review aims to outline the current knowledge of the role and the immunosuppressive properties of MDSC and Treg within the tumor microenvironment (TME). Furthermore, we will discuss the importance of the functional crosstalk between MDSC and Treg for immunosuppression, issuing particularly the role of cell adhesion molecules. Lastly, we will depict the impact of this interaction for cancer research and discuss several strategies aimed to target these pathways for tumor therapy.Immune checkpoint inhibitors (ICI) have led to profound and durable tumor regression in some patients with metastatic cancer diseases. However, many patients still do not derive benefit from immunotherapy. Here, the accumulation of immunosuppressive cell populations within the tumor microenvironment (TME), such as myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), and regulatory T cells (Treg), contributes to the development of immune resistance. MDSC and Treg expand systematically in tumor patients and inhibit T cell activation and T effector cell function. Numerous studies have shown that the immunosuppressive mechanisms exerted by those inhibitory cell populations comprise soluble immunomodulatory mediators and receptor interactions. The latter are also required for the crosstalk of MDSC and Treg, raising questions about the relevance of cell–cell contacts for the establishment of their inhibitory properties. This review aims to outline the current knowledge on the crosstalk between these two cell populations, issuing particularly the potential role of cell adhesion molecules. In this regard, we further discuss the relevance of β2 integrins, which are essential for the differentiation and function of leukocytes as well as for MDSC–Treg interaction. Lastly, we aim to describe the impact of such bidirectional crosstalk for basic and applied cancer research and discuss how the targeting of these pathways might pave the way for future approaches in immunotherapy.
Highlights
Immunotherapy with immune checkpoint inhibitors (ICI) has emerged as a promising treatment for many different types of cancer [1], since it has demonstrated stable and impressive tumor regressions even at an advanced stage of disease [1]
We have outlined that the level of myeloid-derived suppressor cells (MDSC)-mediated immunosuppression might be determined by the quantitative amount of MDSC infiltration into the tumor and the extent of their immunosuppressive activity, but it might involve the quality of their functional crosstalk with other immunosuppressive cells within the tumor microenvironment (TME)
A growing body of evidence describes a tight crosstalk between tumor-infiltrating MDSC and Treg within the TME, which is mediated by cell–cell interactions, soluble mediators, and metabolic pathways
Summary
Immunotherapy with immune checkpoint inhibitors (ICI) has emerged as a promising treatment for many different types of cancer [1], since it has demonstrated stable and impressive tumor regressions even at an advanced stage of disease [1]. To the immunosuppressive effects conferred by soluble mediators and leukocyte receptor interactions, the extensive infiltration of the tumor by immunosuppressive cell populations, such as tumor-associated macrophages (TAM) [16,17], myeloid-derived suppressor cells (MDSC) [18], and regulatory T cells (Treg) [19,20], has been identified as a major driver of the pro-tumorigenic transformation in the TME The presence of these immunosuppressive cells hampers effector T cell induction and recruitment as well as the capability of both natural killer (NK) cells and antigen-presenting cells (APC) to exert effective tumor surveillance, leading to a profound inhibition of the anti-tumor immune response [21]. MDSC and Treg has recently been proposed to be a powerful barrier counter-acting antitumoral immune responses, this review is dedicated to give insights into the potential role of cell–cell contacts as a prerequisite for the immunosuppressive mechanisms in the TME, leading to tumor immune evasion This in consequence facilitates cancer progression and the development of metastases [24]. This review aims to outline the potential role of β2 integrins in this critical cell–cell interaction within an immunosuppressive TME
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