Cancer progression often benefits from the selective conditions present in the tumour microenvironment, such as the presence of cancer-associated fibroblasts (CAFs), deregulated ECM deposition, expanded vascularisation and repression of the immune response. Generation of a hypoxic environment and activation of its main effector, hypoxia-inducible factor-1 (HIF-1), are common features of advanced cancers. In addition to the impact on tumour cell biology, the influence that hypoxia exerts on the surrounding cells represents a critical step in the tumorigenic process. Hypoxia indeed enables a number of events in the tumour microenvironment that lead to the expansion of aggressive clones from heterogeneous tumour cells and promote a lethal phenotype. In this article, we review the most relevant findings describing the influence of hypoxia and the contribution of HIF activation on the major components of the tumour microenvironment, and we summarise their role in cancer development and progression.

/pdf/the-hypoxic-tumour-microenvironment-4843dw6kw7.pdf

The hypoxic tumour microenvironment.

The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and others with minimal to no clinical benefit. An important aspect associated with this discrepancy in patient response is the immune-suppressive effects elicited by the tumour microenvironment (TME). Immune suppression plays a pivotal role in regulating cancer progression, metastasis, and reducing immunotherapy success. Most notably, myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have potent mechanisms to inhibit T-cell and NK-cell activity to promote tumour growth, development of the pre-metastatic niche, and contribute to resistance to immunotherapy. Accumulating research indicates that MDSC can be a therapeutic target to alleviate their pro-tumourigenic functions and immunosuppressive activities to bolster the efficacy of checkpoint inhibitors. In this review, we provide an overview of the general immunotherapeutic approaches and discuss the characterisation, expansion, and activities of MDSCs with the current treatments used to target them either as a single therapeutic target or synergistically in combination with immunotherapy.

https://www.mdpi.com/2073-4409/9/3/561/pdf

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

The crucial roles of oxidative stress and inflammation in the development of hepatic diseases have been unraveled and emphasized for decades. From steatosis to fibrosis, cirrhosis and liver cancer, hepatic oxidative stress, and inflammation are sustained and participated in this pathological progressive process. Notably, increasing evidences showed that oxidative stress and inflammation are tightly related, which are regarded as essential partners that present simultaneously and interact with each other in various pathological conditions, creating a vicious cycle to aggravate the hepatic diseases. Clarifying the interaction of oxidative stress and inflammation is of great importance to provide new directions and targets for developing therapeutic intervention. Herein, this review is concerned with the regulation and interdependence of oxidative stress and inflammation in a variety of liver diseases. In addition to classical mediators and signaling, particular emphasis is placed upon immune suppression, a potential linkage of oxidative stress and inflammation, to provide new inspiration for the treatment of liver diseases. Furthermore, since antioxidation and anti-inflammation have been extensively attempted as the strategies for treatment of liver diseases, the application of herbal medicines and their derived compounds that protect liver from injury via regulating oxidative stress and inflammation collectively were reviewed and discussed.

/pdf/insights-into-the-role-and-interdependence-of-oxidative-14sprcarkj.pdf

Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases

Metformin is a broadly prescribed drug for type 2 diabetes that exerts antitumor activity, yet the mechanisms underlying this activity remain unclear. We show here that metformin treatment blocks the suppressive function of myeloid-derived suppressor cells (MDSC) in patients with ovarian cancer by downregulating the expression and ectoenzymatic activity of CD39 and CD73 on monocytic and polymononuclear MDSC subsets. Metformin triggered activation of AMP-activated protein kinase α and subsequently suppressed hypoxia-inducible factor α, which was critical for induction of CD39/CD73 expression in MDSC. Furthermore, metformin treatment correlated with longer overall survival in diabetic patients with ovarian cancer, which was accompanied by a metformin-induced reduction in the frequency of circulating CD39 + CD73 + MDSC and a concomitant increase in the antitumor activities of circulating CD8 + T cells. Our results highlight a direct effect of metformin on MDSC and suggest that metformin may yield clinical benefit through improvement of antitumor T-cell immunity by dampening CD39/CD73-dependent MDSC immunosuppression in ovarian cancer patients. Significance: The antitumor activity of an antidiabetes drug is attributable to reduced immunosuppressive activity of myeloid-derived tumor suppressor cells. Cancer Res; 78(7); 1779–91. ©2018 AACR .

/pdf/metformin-induced-reduction-of-cd39-and-cd73-blocks-myeloid-jvaoresyow.pdf

Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer

Hypoxic tumor microenvironment is a common feature of solid tumors and is associated with aggressiveness and poor patient outcomes. A continuous interference between cancer cells and stromal cells within the hypoxic microenvironment has been uncovered for its importance in cancer development and treatment responsiveness. Exosomes, initially considered as “garbage bins” for unwanted material from cells, are now elucidated to perform a variety of functions that involve interactions within the cellular microenvironment due to their ability to carry numerous cargoes, including lipids, proteins, nucleic acids, and metabolites. Exosome-mediated continuous interference between cancer cells and stroma are believed to regulate hypoxia-adaptation and to rebuild the microenvironment in return. In this review, we will discuss the knowledge in literature with respect to the exosome-mediated multi-directional and mutual signal transmission among the variety of cell types within hypoxic cancer microenvironment.

/pdf/exosome-orchestrated-hypoxic-tumor-microenvironment-2pfj6rynaa.pdf

Exosome-orchestrated hypoxic tumor microenvironment.

Myeloid-derived suppressor cells (MDSC) display an immature phenotype that may assume a classically activated (M1) or alternatively activated phenotype (M2) in tumors. In this study, we investigated metabolic mechanisms underlying the differentiation of MDSCs into M1 or M2 myeloid lineage and their effect on cancer pathophysiology. We found that SIRT1 deficiency in MDSCs directs a specific switch to M1 lineage when cells enter the periphery from bone marrow, decreasing the suppressive function in favor of a proinflammatory M1 phenotype associated with tumor cell attack. Glycolytic activation through the mTOR–hypoxia-inducible factor1a (HIF-1a) pathway was required for differentiation to the M1 phenotype, which conferred protection against tumors. Our results define the essential nature of a SIRT1–mTOR/HIF-1a glycolytic pathway in determining MDSC differentiation, with implications for metabolic reprogramming as a cancer therapeutic approach. Cancer Res; 74(3); 1–11. � 2013 AACR.

SIRT1 Limits the Function and Fate of Myeloid-Derived Suppressor Cells in Tumors by Orchestrating HIF-1a-

The mTOR pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct the innate and adaptive immune responses. MDSCs are a heterogeneous cell population that plays a crucial regulatory effect in immune-related diseases. However, whether mTOR signaling affects the functions of MDSCs remains largely unknown. Here, we show that mTOR signaling is a pivotal negative determinant of MDSC recruitment in IMH disease. In the context of IMH, inhibition of mTOR with rapamycin in CD11bGr1 MDSCs mediates protection against IMH and serves as a functional, suppressive immune modulator that results in increased CD11bGr1Ly6C high MDSC recruitment to inflammatory sites. In agreement with this, mTOR down-regulation promotes CD11bGr1Ly6C high MDSC migration in vitro and in vivo. Mechanistically, mTOR activity down-regulation in MDSCs induced iNOS expression and NO production. Pharmacologic inhibition of iNOS completely eliminated MDSC recruitment. This study identifies MDSCs as an essential component for protection against IMH following rapamycin treatment. Rapamycin treatment or mTOR inhibition promotes CD11bGr1Ly6C high MDSC recruitment and is critically required for protection against hepatic injury. This study further validates the targeting of mTOR signaling as a potential therapeutic approach to IMH-related diseases. J. Leukoc. Biol. 95: 961–970; 2014.

suppressor cells in protecting against murine immunological hepatic injury

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SIRT1 Limits the Function and Fate of Myeloid-Derived Suppressor Cells in Tumors by Orchestrating HIF-1a-

suppressor cells in protecting against murine immunological hepatic injury

Myeloid-derived suppressor cells in immunity and