Bringing macrophages to the frontline against cancer: current Immunotherapies targeting macrophages

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Macrophages are found in all tissues and display outstanding functional diversity. From embryo to birth and throughout adult life, they play critical roles in development, homeostasis, tissue repair, immunity, and, importantly, in the control of cancer growth. In this review, we will briefly detail the multi-functional, protumoral, and antitumoral roles of macrophages in the tumor microenvironment. Our objective is to focus on the ever-growing therapeutic opportunities, with promising preclinical and clinical results developed in recent years, to modulate the contribution of macrophages in oncologic diseases. While the majority of cancer immunotherapies target T cells, we believe that macrophages have a promising therapeutic potential as tumoricidal effectors and in mobilizing their surroundings towards antitumor immunity to efficiently limit cancer progression.This work was supported by an iMM-Laço research grant and the Fundacão para a Ciência e Tecnologia through a research grant (PTDC/MED-IMU/30948/2017) and a personal fellowship (CEECIND/00697/2018) received by K.S. and a PhD fellowship (SFRH/BD/144792/2019) to C.J. This work was also kindly backed by the COST Action BM1404 Mye-EUNITER (http://www.mye-euniter.eu accessed on 26 November 2018). COST is supported by the EU Framework Program Horizon 2020.info:eu-repo/semantics/publishedVersio

Lipid rafts in cancer chemotherapy

[ES]La continua proliferación de las células tumorales implica una gran demanda de síntesis de nuevas membranas. Ya al principio del siglo 20 se observó una mayor acumulación de colesterol en tumores y en los tejidos adyacentes. Se comenzó a discutir la importancia del colesterol en la progresión tumoral cuando se observó una acumulación irregular en células malignas y su entorno, consecuencia de la alta tasa de proliferación de las células cancerosas, conllevando a una gran demanda de síntesis de nuevas membranas. El descubrimiento de la existencia de microdominios de membrana lipid raft en células normales, ricos en colesterol y especializados en señalización, llevo al estudio del papel de estos dominios en procesos aberrantes y patológicos como la oncogénesis y de metástasis. Estudios recientes demuestran que los dominios de membrana raft están implicados en la agresividad y crecimiento del tumor. Se ha descrito una nueva clase de compuestos denominados lípidos antitumorales (ATLs), los más conocidos perifosina y edelfosina, capaces de inducir apoptosis selectivamente en células malignas mediante un proceso dependiente de microdominios de membrana rafts. Estudios biofísicos han demostrado que el ATL edelfosina posee afinidad por colesterol. Estos compuestos se acumulan en microdominios rafts de células malignas activando la apoptosis por movilización del receptor de muerte Fas/CD95 hacia dominios rafts, de forma independiente de su ligando natural FasL/CD95L, y reclutando proteínas señalizadoras de apoptosis downstream. La incubación con ATLs activa, mediante la reorganización de los dominios de membrana rafts en células tumorales, las vías apoptóticas extrínseca (receptores de muerte) e intrínseca (mitocondrial), vías que se encuentran generalmente bloqueadas en células tumorales e inhibe la activación de la ruta PI3K/Akt, dependiente de la integridad de los raft. Asímismo, se ha descrito que en tumores hay reclutamiento de Fas/CD95 en lipid rafts por compuestos que son químicamente diferentes a los ATLs, como el cisplatino, resveratrol, entre otros, evidenciando que este mecanismo es más general de lo que se creía inicialmente. Algunos estudios sugieren la posibilidad de que este fenómeno sea una consecuencia de la inhibición de PI3K/Akt, conllevando a la activación de Fas/CD95 en lipid rafts, por un mecanismo todavía desconocido.[EN] The ongoing proliferation of tumor cells involves a great demand for synthesis of new membranes . Since the early 20th century increased cholesterol accumulation in tumors and adjacent tissues was observed. He began to discuss the importance of cholesterol in tumor progression when an irregular accumulation in malignant cells and their environment due to the high rate of proliferation of cancer cells , leading to a high demand for synthesis of new membranes was observed. The discovery of the existence of lipid raft membrane microdomains in normal cells , high cholesterol and specialized in signage, led to the study of the role of these domains in aberrant and pathological processes such as oncogenesis and metastasis. Recent studies show that membrane raft domains are involved in tumor growth and aggressiveness . Described a new class of antitumor compounds termed lipids ( ATLs ) , the best known perifosine and edelfosine , capable of inducing apoptosis selectively in cancer cells by a process dependent membrane microdomains rafts . Biophysical studies have shown that the affinity has edelfosine ATL cholesterol . These compounds accumulate in malignant cell rafts microdomains activating apoptosis death receptor mobilization Fas/CD95 to rafts domains independently of its natural ligand FasL/CD95L and apoptosis by recruiting downstream signaling proteins . Incubation with active ATLs through reorganization of membrane rafts domains on tumor cells, the extrinsic apoptotic pathways (death receptor ) and intrinsic (mitochondrial) , pathways are typically locked in tumor cells and inhibits the activation of the path PI3K/Akt dependent raft integrity

Bringing Macrophages to the Frontline against Cancer: Current Immunotherapies Targeting Macrophages

Macrophages are found in all tissues and display outstanding functional diversity. From embryo to birth and throughout adult life, they play critical roles in development, homeostasis, tissue repair, immunity, and, importantly, in the control of cancer growth. In this review, we will briefly detail the multi-functional, protumoral, and antitumoral roles of macrophages in the tumor microenvironment. Our objective is to focus on the ever-growing therapeutic opportunities, with promising preclinical and clinical results developed in recent years, to modulate the contribution of macrophages in oncologic diseases. While the majority of cancer immunotherapies target T cells, we believe that macrophages have a promising therapeutic potential as tumoricidal effectors and in mobilizing their surroundings towards antitumor immunity to efficiently limit cancer progression

Focus on Extracellular Vesicles: New Frontiers of Cell-to-Cell Communication in Cancer

Extracellular Vesicles (EVs) have received considerable attention in recent years, both as mediators of intercellular communication pathways that lead to tumor progression, and as potential sources for discovery of novel cancer biomarkers. For many years, research on EVs has mainly investigated either the mechanism of biogenesis and cargo selection and incorporation, or the methods of EV isolation from available body fluids for biomarker discovery. Recent studies have highlighted the existence of different populations of cancer-derived EVs, with distinct molecular cargo, thus pointing to the possibility that the various EV populations might play diverse roles in cancer and that this does not happen randomly. However, data attributing cancer specific intercellular functions to given populations of EVs are still limited. A deeper functional, biochemical and molecular characterization of the various EV classes might identify more selective clinical markers, and significantly advance our knowledge of the pathogenesis and disease progression of many cancer types

A scalable filtration method for high throughput screening based on cell deformability

Cell deformability is a label-free biomarker of cell state in physiological and disease contexts ranging from stem cell differentiation to cancer progression. Harnessing deformability as a phenotype for screening applications requires a method that can simultaneously measure the deformability of hundreds of cell samples and can interface with existing high throughput facilities. Here we present a scalable cell filtration device, which relies on the pressure-driven deformation of cells through a series of pillars that are separated by micron-scale gaps on the timescale of seconds: less deformable cells occlude the gaps more readily than more deformable cells, resulting in decreased filtrate volume which is measured using a plate reader. The key innovation in this method is that we design customized arrays of individual filtration devices in a standard 96-well format using soft lithography, which enables multiwell input samples and filtrate outputs to be processed with higher throughput using automated pipette arrays and plate readers. To validate high throughput filtration to detect changes in cell deformability, we show the differential filtration of human ovarian cancer cells that have acquired cisplatin-resistance, which is corroborated with cell stiffness measurements using quantitative deformability cytometry. We also demonstrate differences in the filtration of human cancer cell lines, including ovarian cancer cells that overexpress transcription factors (Snail, Slug), which are implicated in epithelial-to-mesenchymal transition; breast cancer cells (malignant versus benign); and prostate cancer cells (highly versus weekly metastatic). We additionally show how the filtration of ovarian cancer cells is affected by treatment with drugs known to perturb the cytoskeleton and the nucleus. Our results across multiple cancer cell types with both genetic and pharmacologic manipulations demonstrate the potential of this scalable filtration device to screen cells based on their deformability

Large oncosomes contain distinct protein cargo and represent a separate functional class of tumor-derived extracellular vesicles

Large oncosomes (LO) are atypically large (1-10μm diameter) cancer-derived extracellular vesicles (EVs), originating from the shedding of membrane blebs and associated with advanced disease. We report that 25% of the proteins, identified by a quantitative proteomics analysis, are differentially represented in large and nano-sized EVs from prostate cancer cells. Proteins enriched in large EVs included enzymes involved in glucose, glutamine and amino acid metabolism, all metabolic processes relevant to cancer. Glutamine metabolism was altered in cancer cells exposed to large EVs, an effect that was not observed upon treatment with exosomes. Large EVs exhibited discrete buoyant densities in iodixanol (OptiPrepTM) gradients. Fluorescent microscopy of large EVs revealed an appearance consistent with LO morphology, indicating that these structures can be categorized as LO. Among the proteins enriched in LO, cytokeratin 18 (CK18) was one of the most abundant (within the top 5th percentile) and was used to develop an assay to detect LO in the circulation and tissues of mice and patients with prostate cancer. These observations indicate that LO represent a discrete EV type that may play a distinct role in tumor progression and that may be a source of cancer-specific markers

ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis

Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC