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      Molecular Profiling and Functional Analysis of Macrophage-Derived Tumor Extracellular Vesicles

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          Summary

          Extracellular vesicles (EVs), including exosomes, modulate multiple aspects of cancer biology. Tumor-associated macrophages (TAMs) secrete EVs, but their molecular features and functions are poorly characterized. Here, we report methodology for the enrichment, quantification, and proteomic and lipidomic analysis of EVs released from mouse TAMs (TAM-EVs). Compared to source TAMs, TAM-EVs present molecular profiles associated with a Th1/M1 polarization signature, enhanced inflammation and immune response, and a more favorable patient prognosis. Accordingly, enriched TAM-EV preparations promote T cell proliferation and activation ex vivo. TAM-EVs also contain bioactive lipids and biosynthetic enzymes, which may alter pro-inflammatory signaling in the cancer cells. Thus, whereas TAMs are largely immunosuppressive, their EVs may have the potential to stimulate, rather than limit, anti-tumor immunity.

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          Highlights

          • •

            Macrophages produce abundant extracellular vesicles in tumors

          • •

            Macrophage-derived extracellular vesicles (TAM-EVs) display unique proteomic profiles

          • •

            TAM-EVs enhance thromboxane synthesis in cancer cells

          • •

            TAM-EVs promote, rather than limit, T cell proliferation and activation

          Abstract

          Cianciaruso et al. develop methods for the analysis of extracellular vesicles secreted by macrophages in mouse tumors (TAM-EVs). Proteomic and lipidomic profiling indicates that TAM-EVs carry modulators of inflammation and lipid metabolism that could influence the properties of the tumor immune microenvironment.

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          The CRAPome: a Contaminant Repository for Affinity Purification Mass Spectrometry Data

          Dattatreya Mellacheruvu, Zachary Wright, Amber L Couzens … (2013)
          Affinity purification coupled with mass spectrometry (AP-MS) is now a widely used approach for the identification of protein-protein interactions. However, for any given protein of interest, determining which of the identified polypeptides represent bona fide interactors versus those that are background contaminants (e.g. proteins that interact with the solid-phase support, affinity reagent or epitope tag) is a challenging task. While the standard approach is to identify nonspecific interactions using one or more negative controls, most small-scale AP-MS studies do not capture a complete, accurate background protein set. Fortunately, negative controls are largely bait-independent. Hence, aggregating negative controls from multiple AP-MS studies can increase coverage and improve the characterization of background associated with a given experimental protocol. Here we present the Contaminant Repository for Affinity Purification (the CRAPome) and describe the use of this resource to score protein-protein interactions. The repository (currently available for Homo sapiens and Saccharomyces cerevisiae) and computational tools are freely available online at www.crapome.org.
          Article 0 comments Cited 687 times – based on 0 reviews     Review now
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            T cell receptor antagonist peptides induce positive selection.

            Kristin A. Hogquist, Stephen C. Jameson, William R. Heath … (1994)
            We have used organ culture of fetal thymic lobes from T cell receptor (TCR) transgenic beta 2M(-/-) mice to study the role of peptides in positive selection. The TCR used was from a CD8+ T cell specific for ovalbumin 257-264 in the context of Kb. Several peptides with the ability to induce positive selection were identified. These peptide-selected thymocytes have the same phenotype as mature CD8+ T cells and can respond to antigen. Those peptides with the ability to induce positive selection were all variants of the antigenic peptide and were identified as TCR antagonist peptides for this receptor. One peptide tested, E1, induced positive selection on the beta 2M(-/-) background but negative selection on the beta 2M(+/-) background. These results show that the process of positive selection is exquisitely peptide specific and sensitive to extremely low ligand density and support the notion that low efficacy ligands mediate positive selection.
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              Conditional gene targeting in macrophages and granulocytes using LysMcre mice.

              B. Clausen, C Burkhardt, W. Reith … (1999)
              Conditional mutagenesis in mice has recently been made possible through the combination of gene targeting techniques and site-directed mutagenesis, using the bacteriophage P1-derived Cre/loxP recombination system. The versatility of this approach depends on the availability of mouse mutants in which the recombinase Cre is expressed in the appropriate cell lineages or tissues. Here we report the generation of mice that express Cre in myeloid cells due to targeted insertion of the cre cDNA into their endogenous M lysozyme locus. In double mutant mice harboring both the LysMcre allele and one of two different loxP-flanked target genes tested, a deletion efficiency of 83-98% was determined in mature macrophages and near 100% in granulocytes. Partial deletion (16%) could be detected in CD11c+ splenic dendritic cells which are closely related to the monocyte/macrophage lineage. In contrast, no significant deletion was observed in tail DNA or purified T and B cells. Taken together, LysMcre mice allow for both specific and highly efficient Cre-mediated deletion of loxP-flanked target genes in myeloid cells.
              Article 0 comments Cited 658 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Chiara Cianciaruso
                Michele De Palma
                Journal
                Journal ID (nlm-ta): Cell Rep
                Journal ID (iso-abbrev): Cell Rep
                Title: Cell Reports
                Publisher: Cell Press
                ISSN (Electronic): 2211-1247
                Publication date PMC-release: 04 June 2019
                Publication date Collection: 04 June 2019
                Publication date (Electronic): 04 June 2019
                Volume: 27
                Issue: 10
                Pages: 3062-3080.e11
                Affiliations
                [1 ]Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
                [2 ]Proteomics Core Facility, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
                [3 ]Flow Cytometry Core Facility, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
                [4 ]Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, 1005 Lausanne, Switzerland
                [5 ]Roche Innovation Center Munich, Roche Pharma Research and Early Development, 82377 Penzberg, Germany
                Author notes
                [∗ ]Corresponding author chiara.cianciaruso@ 123456epfl.ch
                [∗∗ ]Corresponding author michele.depalma@ 123456epfl.ch
                [6]

                These authors contributed equally

                [7]

                Lead Contact

                Article
                Publisher ID: S2211-1247(19)30619-9
                DOI: 10.1016/j.celrep.2019.05.008
                PMC ID: 6581796
                PubMed ID: 31167148
                SO-VID: 8de98f12-8c2e-4852-bbfc-f4c66347a121
                Copyright © © 2019 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 23 January 2019
                Date revision received : 10 April 2019
                Date accepted : 30 April 2019
                Categories
                Subject: Article

                ScienceOpen disciplines: Cell biology
                Keywords: extracellular vesicle,exosome,tumor microenvironment,tumor-associated macrophage,proteomics,lipidomics,lipid metabolism,inflammation,t cell response
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: extracellular vesicle, exosome, tumor microenvironment, tumor-associated macrophage, proteomics, lipidomics, lipid metabolism, inflammation, t cell response

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