Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids.

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a long latency period and dismal prognosis. Recently, tazemetostat (EPZ-6438), an inhibitor of the histone methyltransferase EZH2, has entered clinical trials due to the antiproliferative effects reported on MPM cells. However, the direct and indirect effects of epigenetic reprogramming on the tumor microenvironment are hitherto unexplored. To investigate the impact of tumor-associated macrophages (TAMs) on MPM cell responsiveness to tazemetostat, we developed a three-dimensional MPM spheroid model that recapitulates in vitro, both monocytes' recruitment in tumors and their functional differentiation toward a TAM-like phenotype (Mo-TAMs). Along with an increased expression of genes for monocyte chemoattractants, inhibitory immune checkpoints, immunosuppressive and M2-like molecules, Mo-TAMs promote tumor cell proliferation and spreading. Prolonged treatment of MPM spheroids with tazemetostat enhances both the recruitment of Mo-TAMs and the expression of their protumor phenotype. Therefore, Mo-TAMs profoundly suppress the antiproliferative effects due to EZH2 inhibition in MPM cells. Overall, our findings indicate that TAMs are a driving force for MPM growth, progression, and resistance to tazemetostat; therefore, strategies of TAM depletion might be evaluated to improve the therapeutic efficacy of pharmacological inhibition of EZH2.

The Macrophages-Microbiota Interplay in Colorectal Cancer (CRC)-Related Inflammation: Prognostic and Therapeutic Significance.

Tumor-associated macrophages (TAMs) are the main population of myeloid cells infiltrating solid tumors and the pivotal orchestrators of cancer-promoting inflammation. However, due to their exceptional plasticity, macrophages can be also key effector cells and powerful activators of adaptive anti-tumor immunity. This functional heterogeneity is emerging in human tumors, colorectal cancer (CRC) in particular, where the dynamic co-existence of different macrophage subtypes influences tumor development, outcome, and response to therapies. Intestinal macrophages are in close interaction with enteric microbiota, which contributes to carcinogenesis and affects treatment outcomes. This interplay may be particularly relevant in CRC, one of the most prevalent and lethal cancer types in the world. Therefore, both macrophages and intestinal microbiota are considered promising prognostic indicators and valuable targets for new therapeutic approaches. Here, we discuss the current understanding of the molecular circuits underlying the interplay between macrophages and microbiota in CRC development, progression, and response to both conventional therapies and immunotherapies.

Metabolic influence on the differentiation of suppressive myeloid cells in cancer.

New evidences indicate that the metabolic instruction of immunity (immune metabolism) results from the integration of cell metabolism and whole-body metabolism, which are both influenced by nutrition, microbiome metabolites and disease-driven metabolism (e.g. cancer metabolism). Cancer metabolism influences the immunological homeostasis and promotes immune alterations that support disease progression, hence influencing the clinical outcome. Cancer cells display increased glucose uptake and fermentation of glucose to lactate, even in the presence of completely functioning mitochondria. A major side effect of this event is immunosuppression, characterized by limited immunogenicity of cancer cells and restriction of the therapeutic efficacy of anticancer immunotherapy. Here, we discuss how the metabolism of myeloid cells associated with cancer contributes to the differentiation of their suppressive phenotype and therefore to cancer immune evasion.

NAMPT: A pleiotropic modulator of monocytes and macrophages.

Nicotinamide phosphoribosyltransferase (NAMPT) is the bottleneck enzyme of the NAD salvage pathway and thereby is a controller of intracellular NAD concentrations. It has been long known that the same enzyme can be secreted by a number of cell types and acts as a cytokine, although its receptor is at present unknown. Investigational compounds have been developed that target the enzymatic activity as well as the extracellular action (i.e. neutralizing antibodies). The present contribution reviews the evidence that links intracellular and extracellular NAMPT to myeloid biology, for example governing monocyte/macrophage differentiation, polarization and migration. Furthermore, it reviews the evidence that links this protein to some disorders in which myeloid cells have a prominent role (acute infarct, inflammatory bowel disease, acute lung injury and rheumatoid arthritis) and the data showing that inhibition of the enzymatic activity or the neutralization of the cytokine is beneficial in preclinical animal models.

Myeloid-Derived Suppressor Cells: Ductile Targets in Disease.

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells with major regulatory functions and rise during pathological conditions, including cancer, infections and autoimmune conditions. MDSC expansion is generally linked to inflammatory processes that emerge in response to stable immunological stress, which alter both magnitude and quality of the myelopoietic output. Inability to reinstate physiological myelopoiesis would fall in an "emergency state" that perpetually reprograms myeloid cells toward suppressive functions. While differentiation and reprogramming of myeloid cells toward an immunosuppressive phenotype can be considered the result of a multistep process that originates in the bone marrow and culminates in the tumor microenvironment, the identification of its driving events may offer potential therapeutic approaches in different pathologies. Indeed, whereas expansion of MDSCs, in both murine and human tumor bearers, results in reduced immune surveillance and antitumor cytotoxicity, placing an obstacle to the effectiveness of anticancer therapies, adoptive transfer of MDSCs has shown therapeutic benefits in autoimmune disorders. Here, we describe relevant mechanisms of myeloid cell reprogramming leading to generation of suppressive MDSCs and discuss their therapeutic ductility in disease.