Here, the authors discuss how the immune activities of myeloid cells, such as macrophages and dendritic cells, are affected by the immunosuppressive tumour environment. They propose that tumours can evade the immune system by promoting aberrant differentiation and function of the entire myeloid system.

Coordinated regulation of myeloid cells by tumours

The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient's tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.

Understanding the tumor immune microenvironment (TIME) for effective therapy.

Tumour formation involves the co-evolution of neoplastic cells together with extracellular matrix, tumour vasculature and immune cells Successful outgrowth of tumours and eventual metastasis is not determined solely by genetic alterations in tumour cells, but also by the fitness advantage such mutations confer in a given environment As fitness is context dependent, evaluating tumours as complete organs, and not simply as masses of transformed epithelial cells, becomes paramount The dynamic tumour topography varies drastically even throughout the same lesion Heterologous cell types within tumours can actively influence therapeutic response and shape resistance

Influence of tumour micro-environment heterogeneity on therapeutic response

Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions of MDSC to tumour progression through both immune-mediated mechanisms and those not directly associated with immune suppression. MDSC are the subject of intensive research with >500 papers published in 2015 alone. However, the phenotypic, morphological and functional heterogeneity of these cells generates confusion in investigation and analysis of their roles in inflammatory responses. The purpose of this communication is to suggest characterization standards in the burgeoning field of MDSC research.

/pdf/recommendations-for-myeloid-derived-suppressor-cell-4c71rinakd.pdf

Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards

https://www.cell.com/trends/immunology/pdf/S1471-4906(16)00005-3.pdf

The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment.

Priming of the organ-specific premetastatic sites is thought to be an important yet incompletely understood step during metastasis. In this study, we show that the metastatic tumors we examined overexpress granulocyte-colony stimulating factor (G-CSF), which expands and mobilizes Ly6G+Ly6C+ granulocytes and facilitates their subsequent homing at distant organs even before the arrival of tumor cells. Moreover, G-CSF–mobilized Ly6G+Ly6C+ cells produce the Bv8 protein, which has been implicated in angiogenesis and mobilization of myeloid cells. Anti–G-CSF or anti-Bv8 antibodies significantly reduced lung metastasis. Transplantation of Bv8 null fetal liver cells into lethally irradiated hosts also reduced metastasis. We identified an unexpected role for Bv8: the ability to stimulate tumor cell migration through activation of one of the Bv8 receptors, prokineticin receptor (PKR)-1. Finally, we show that administration of recombinant G-CSF is sufficient to increase the numbers of Ly6G+Ly6C+ cells in organ-specific metastatic sites and results in enhanced metastatic ability of several tumors.

https://www.pnas.org/content/pnas/107/50/21248.full.pdf

Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes

Recent studies suggest that tumor-associated CD11b+Gr1+ myeloid cells contribute to refractoriness to antiangiogenic therapy with an anti-VEGF-A antibody. However, the mechanisms of peripheral mobilization and tumor-homing of CD11b+Gr1+ cells are unclear. Here, we show that, compared with other cytokines [granulocyte-macrophage colony stimulating factor (GM-CSF), stromal derived factor 1α, and placenta growth factor], G-CSF and the G-CSF-induced Bv8 protein have preferential expression in refractory tumors. Treatment of refractory tumors with the combination of anti-VEGF and anti-G-CSF (or anti-Bv8) reduced tumor growth compared with anti-VEGF-A monotherapy. Anti-G-CSF treatment dramatically suppressed circulating or tumor-associated CD11b+Gr1+ cells, reduced Bv8 levels, and affected the tumor vasculature. Conversely, G-CSF delivery to animals bearing anti-VEGF sensitive tumors resulted in reduced responsiveness to anti-VEGF-A treatment through induction of Bv8-dependent angiogenesis. We conclude that, at least in the models examined, G-CSF expression by tumor or stromal cells is a determinant of refractoriness to anti-VEGF-A treatment.

https://www.pnas.org/content/pnas/106/16/6742.full.pdf

G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models

Purpose: Bv8, also known as prokineticin 2, has been recently shown to be a mediator of myeloid cell–dependent tumor angiogenesis in mouse models We wished to determine whether these findings might be potentially relevant to human disease Experimental Design: We characterized Bv8 expression in human blood cells in vitro and in vivo , and did Bv8 immunohistochemistry in human tumor sections We also partially purified Bv8 from human neutrophils and tested its bioactivity Results: We found that Bv8 expression is regulated by several cytokines in a cell type–specific fashion Both granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor induced Bv8 expression in neutrophils and bone marrow cells, whereas interleukin 10 up-regulated Bv8 expression in monocytes and lymphocytes Bv8 potently promoted neutrophil chemotaxis Bv8 protein isolated from human neutrophils was found to be biologically active Of the two receptors for Bv8 [prokineticin receptor 1(PKR1)/endocrine gland–derived vascular endothelial growth factor receptor 1 (EG-VEGFR1) and PKR2/EG-VEGFR2], only PKR2/EG-VEGFR2 was detectable in human neutrophils Also, we found a marked up-regulation of Bv8 mRNA and protein in peripheral blood mononuclear cells from G-CSF–treated donors compared with those from untreated individuals, verifying our in vitro observations Finally, immunohistochemistry showed Bv8 expression in neutrophils infiltrating human tumors Conclusions: These results provide the basis for further investigation of the pathophysiologic role of Bv8 in human tumors and inflammatory disorders and, potentially, for therapeutic application of Bv8 inhibitors

https://clincancerres.aacrjournals.org/content/clincanres/15/8/2675.full.pdf

Xueping Qu

Papers

Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes

G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models

Characterization and Regulation of Bv8 in Human Blood Cells

Induction of Bv8 Expression by Granulocyte Colony-stimulating Factor in CD11b+Gr1+ Cells KEY ROLE OF Stat3 SIGNALING