Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells generated during a large array of pathologic conditions ranging from cancer to obesity. These cells represent a pathologic state of activation of monocytes and relatively immature neutrophils. MDSCs are characterized by a distinct set of genomic and biochemical features, and can, on the basis of recent findings, be distinguished by specific surface molecules. The salient feature of these cells is their ability to inhibit T cell function and thus contribute to the pathogenesis of various diseases. In this Review, we discuss the origin and nature of these cells; their distinctive features; and their biological roles in cancer, infectious diseases, autoimmunity, obesity and pregnancy.

Myeloid-derived suppressor cells coming of age.

Cells release membrane enclosed nano-sized vesicles termed extracellular vesicles (EVs) that function as mediators of intercellular communication by transferring biological information between cells. Tumor-derived EVs have emerged as important mediators in cancer development and progression, mainly through transfer of their bioactive content which can include oncoproteins, oncogenes, chemokine receptors, as well as soluble factors, transcripts of proteins and miRNAs involved in angiogenesis or inflammation. This transfer has been shown to influence the metastatic behavior of primary tumors. Moreover, tumor-derived EVs have been shown to influence distant cellular niches, establishing favorable microenvironments that support growth of disseminated cancer cells upon their arrival at these pre-metastatic niches. It is generally accepted that cells release a number of major EV populations with distinct biophysical properties and biological functions. Exosomes, microvesicles, and apoptotic bodies are EV populations most widely studied and characterized. They are discriminated based primarily on their intracellular origin. However, increasing evidence suggests that even within these EV populations various subpopulations may exist. This heterogeneity introduces an extra level of complexity in the study of EV biology and function. For example, EV subpopulations could have unique roles in the intricate biological processes underlying cancer biology. Here, we discuss current knowledge regarding the role of subpopulations of EVs in cancer development and progression and highlight the relevance of EV heterogeneity. The position of tetraspanins and integrins therein will be highlighted. Since addressing EV heterogeneity has become essential for the EV field, current and novel techniques for isolating EV subpopulations will also be discussed. Further dissection of EV heterogeneity will advance our understanding of the critical roles of EVs in health and disease.

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Extracellular Vesicle Heterogeneity: Subpopulations, Isolation Techniques, and Diverse Functions in Cancer Progression

The role and importance of neutrophils in cancer has become increasingly apparent over the past decade. Neutrophils accumulate in the peripheral blood of patients with cancer, especially in those with advanced-stage disease, and a high circulating neutrophil-to-lymphocyte ratio is a robust biomarker of poor clinical outcome in various cancers. To date, most studies investigating the role of neutrophils in cancer have involved animal models or investigated the function of circulating human neutrophils. Thus, only limited information is available on the roles of intratumoural neutrophils (also known as tumour-associated neutrophils (TANs)) in patients with cancer. In this Review, we initially describe the evidence correlating the neutrophil-to-lymphocyte ratio with prognosis, followed by a discussion on the predictive value of TANs, which remains debatable, with conflicting data from different cancer types, including variations based on neutrophil location within and/or around the tumour. We then explore available data on the implications of TAN phenotypes and functions for cancer development and progression, highlighting the reported effects of various treatments on TANs and how neutrophils might affect therapeutic efficacy. Finally, we examine the various compounds capable of modulating neutrophils and suggest future research directions that might ultimately enable the manipulation of TANs in patients with cancer.

Tumour-associated neutrophils in patients with cancer

Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation

The immune system has many sophisticated mechanisms to balance an extensive immune response. Distinct immunosuppressive cells could protect from excessive tissue damage and autoimmune disorders. Tumor cells take an advantage of those immunosuppressive mechanisms and establish a strongly immunosuppressive tumor microenvironment (TME), which inhibits anti-tumor immune responses, supporting the disease progression. Myeloid-derived suppressor cells (MDSC) play a crucial role in this immunosuppressive TME. Those cells represent a heterogeneous population of immature myeloid cells with a strong immunosuppressive potential. They inhibit an anti-tumor reactivity of T cells and NK cells. Furthermore, they promote angiogenesis, establish pre-metastatic niches and recruit other immunosuppressive cells such as regulatory T cells. Accumulating evidences demonstrated that the enrichment and activation of MDSC correlated with tumor progression, recurrence, and negative clinical outcome. In the last few years, various pre-clinical studies and clinical trials targeting MDSC showed promising results. In this review, we discuss different therapeutic approaches on MDSC targeting to overcome immunosuppressive TME and enhance the efficiency of current tumor immunotherapies.

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Carolin Blattner

Papers

The Role of Myeloid-Derived Suppressor Cells (MDSC) in Cancer Progression