title: Anti-inflammatory M2 type macrophages characterize metastasized and tyrosine kinase inhibitor-treated gastrointestinal stromal tumors.
abstract: We have made a detailed inventory of the immune infiltrate of gastrointestinal stromal tumors (GISTs), which originate from mesenchymal cells in the intestinal tract. These sarcomas are heavily infiltrated with macrophages and T cells, while immune cells of other lineages were much less abundant. Dissecting the functional subtypes of T cells with multicolor fluorescent microscopy revealed substantial populations of cytotoxic T cells, helper T cells and FoxP3(+) regulatory T cells. The balance of cytotoxic T cells and FoxP3(+) T cells was toward immune suppression. Analysis of the macrophage population also showed a dominance of anti-inflammatory cells, as the M2 type scavenger receptor CD163 was abundantly present. Other subsets of macrophages (CD14(+)CD163(-)) were occasionally detected. M2 type CD163(+) macrophages were associated with the number of infiltrating FoxP3(+) regulatory T cells and twice as many macrophages were found in metastatic GIST compared to primary lesions. Most metastatic GISTs had been treated with the tyrosine kinase inhibitors imatinib and sunitinib, but the high macrophage infiltrate was not related to this treatment. However, imatinib and sunitinib did induce secretion of anti-inflammatory IL-10 in macrophage cultures, indicating that treatment with these inhibitors might contribute to an immune suppressive microenvironment in GIST. Overall, our data reveal a picture of GIST as an active site of tumor-immune interaction in which suppressive mechanisms overrule potential antitumor responses. Tyrosine kinase inhibitors might promote this negative balance.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Minka
authors.initials: M
authors.lastname: van Dongen
authors.forename: Nigel D L
authors.initials: ND
authors.lastname: Savage
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.forename: Inge H
authors.initials: IH
authors.lastname: Briaire-de Bruijn
authors.forename: Kimberley V
authors.initials: KV
authors.lastname: Walburg
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.forename: Thorbald
authors.initials: T
authors.lastname: van Hall
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001549:Benzamides; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000627:therapeutic use; D016753:Interleukin-10 / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D010879:Piperazines / Q000627:therapeutic use; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000378:metabolism; D000077210:Sunitinib; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001549:Benzamides; D000098902:CD163 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D011956:Receptors, Cell Surface; D016753:Interleukin-10; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib