Identification and manipulation of tumor associated macrophages in human cancers

Evading immune destruction and tumor promoting inflammation are important hallmarks in the development of cancer. Macrophages are present in most human tumors and are often associated with bad prognosis. Tumor associated macrophages come in many functional flavors ranging from what is known as classically activated macrophages (M1) associated with acute inflammation and T-cell immunity to immune suppressive macrophages (M2) associated with the promotion of tumor growth. The role of these functionally different myeloid cells is extensively studied in mice tumor models but dissimilarities in markers and receptors make the direct translation to human cancer difficult. This review focuses on recent reports discriminating the type of infiltrating macrophages in human tumors and the environmental cues present that steer their differentiation. Finally, immunotherapeutic approaches to interfere in this process are discussed

Nadelige gezondheidseffecten en ziekten veroorzaakt door blootstelling aan hexamethyleen di-isocyanaat (HDI) : Literatuuronderzoek en consultatie van deskundigen

Dit rapport maakt onderdeel uit van een serie van acht rapporten over het onderzoek naar HDI uit CARC op de POMS-locaties van Defensie. Dit rapport bevat geen afzonderlijke publiekssamenvatting. Een overkoepelende publiekssamenvatting van de acht rapporten is te vinden op de website van het RIVM: "CARC op de POMS-locaties van Defensie: blootstelling en gezondheidsrisico's. Bevindingen uit het onderzoek op hoofdlijnen, met speciale aandacht voor het bestanddeel HDI" RIVM rapport 2020-0017Ministerie van Defensi

Nadelige gezondheidseffecten en ziekten veroorzaakt door blootstelling aan hexamethyleen di-isocyanaat (HDI) : Literatuuronderzoek en consultatie van deskundigen

Dit rapport maakt onderdeel uit van een serie van acht rapporten over het onderzoek naar HDI uit CARC op de POMS-locaties van Defensie. Dit rapport bevat geen afzonderlijke publiekssamenvatting. Een overkoepelende publiekssamenvatting van de acht rapporten is te vinden op de website van het RIVM: "CARC op de POMS-locaties van Defensie: blootstelling en gezondheidsrisico's. Bevindingen uit het onderzoek op hoofdlijnen, met speciale aandacht voor het bestanddeel HDI" RIVM rapport 2020-001

In vitro techniques for assessing neurotoxicity using human IPSC-derived neuronal models

The central nervous system consists of a multitude of different neurons and supporting cells that form networks for transmitting neuronal signals. Proper function of the nervous system depends critically on a wide range of highly regulated processes including intracellular calcium homeostasis, neurotransmitter release, and electrical activity. Due to the diversity of cell types and complexity of signaling processes, the (central) nervous system is very vulnerable to toxic insults. Nowadays, a broad range of approaches and cell models is available to study neurotoxicity. In this chapter we show the applicability of human induced pluripotent stem cell (hiPSC)-derived neuronal co-cultures for in vitro neurotoxicity testing. We demonstrate that immunocytochemistry can be used to visualize networks of cultured cells and to differentiate between different cell types. Live cell imaging and electrophysiology techniques demonstrate that the neuronal networks develop spontaneous activity, including synchronized calcium oscillations that coincide with spontaneous changes in membrane potential as well as spontaneous electrical activity with defined (network) bursting. Importantly, as shown in this chapter, spontaneously active human iPSC-derived neuronal co-cultures are suitable for in vitro neurotoxicity assessment. Future application of live imaging and electrophysiological techniques on hiPSC from different donors and/or patients differentiated in different cell types holds great promise for personalized neurotoxicity assessment and safety screening

Phenotypic skewing of macrophages in vitro by secreted factors from colorectal cancer cells

Macrophages are cells with many important functions in both innate and adaptive immune responses and have been shown to play a complex role in tumor progression since they harbour both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. In many human cancers, infiltrating macrophages have been associated with a poor patient prognosis, and therefore suggested to be mainly of an M2 phenotype. However, we and others have previously shown that increased macrophage density in colorectal cancer (CRC) instead is correlated with an improved prognosis. It is an intriguing question if the different roles played by macrophages in various cancers could be explained by variations in the balance between M1 and M2 macrophage attributes, driven by tumor- or organ-specific factors in the tumor microenvironment of individual cancers. Here, we utilized an in vitro cell culture system of macrophage differentiation to compare differences and similarities in the phenotype (morphology, antigen-presentation, migration, endocytosis, and expression of cytokine and chemokine genes) between M1/M2 and tumor activated macrophages (TAMs), that could explain the positive role of macrophages in CRC. We found that secreted factors from CRC cells induced TAMs of a "mixed" M1/M2 phenotype, which in turn could contribute to a "good inflammatory response". This suggests that re-education of macrophages might allow for important therapeutic advances in the treatment of human cancer.This study was supported by grants from the Swedish Cancer Society (Grant no. CAN 2011/839, Palmqvist) (www.cancerfonden.se); Swedish Research Council (Grant no. B03488901, Palmqvist) (www.vr.se); Cutting-Edge Research Grant from the County Council of Västerbotten, Sweden (Grant no. VLL-132981, Palmqvist); Cancer Research Foundation in Northern Sweden (Grant no. AMP 10-655, Edin) (www.cancerforskningsfonden.se); and Tore Nilssons Foundation (Edin) (www.torenilssonsstiftelse.nu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</p