title: Engagement of myelomonocytic Siglecs by tumor-associated ligands modulates the innate immune response to cancer.
abstract: Certain pathogenic bacteria are known to modulate the innate immune response by decorating themselves with sialic acids, which can engage the myelomonocytic lineage inhibitory receptor Siglec-9, thereby evading immunosurveillance. We hypothesized that the well-known up-regulation of sialoglycoconjugates by tumors might similarly modulate interactions with innate immune cells. Supporting this hypothesis, Siglec-9-expressing myelomonocytic cells found in human tumor samples were accompanied by a strong up-regulation of Siglec-9 ligands. Blockade of Siglec-9 enhanced neutrophil activity against tumor cells in vitro. To investigate the function of inhibitory myelomonocytic Siglecs in vivo we studied mouse Siglec-E, the murine functional equivalent of Siglec-9. Siglec-E-deficient mice showed increased in vivo killing of tumor cells, and this effect was reversed by transgenic Siglec-9 expression in myelomonocytic cells. Siglec-E-deficient mice also showed enhanced immunosurveillance of autologous tumors. However, once tumors were established, they grew faster in Siglec-E-deficient mice. In keeping with this, Siglec-E-deficient macrophages showed a propensity toward a tumor-promoting M2 polarization, indicating a secondary role of CD33-related Siglecs in limiting cancer-promoting inflammation and tumor growth. Thus, we define a previously unidentified impact of inhibitory myelomonocytic Siglecs in cancer biology, with distinct roles that reflect the dual function of myelomonocytic cells in cancer progression. In keeping with this, a human polymorphism that reduced Siglec-9 binding to carcinomas was associated with improved early survival in non-small-cell lung cancer patients, which suggests that Siglec-9 might be therapeutically targeted within the right time frame and stage of disease.
authors.affiliation: Departments of Medicine and Cellular and Molecular Medicine, Glycobiology Research and Training Center, and.
authors.forename: Heinz
authors.initials: H
authors.lastname: Läubli
authors.affiliation: Departments of Medicine and Cellular and Molecular Medicine, Glycobiology Research and Training Center, and.
authors.forename: Oliver M T
authors.initials: OM
authors.lastname: Pearce
authors.affiliation: Departments of Medicine and Cellular and Molecular Medicine, Glycobiology Research and Training Center, and.
authors.forename: Flavio
authors.initials: F
authors.lastname: Schwarz
authors.affiliation: Departments of Medicine and Cellular and Molecular Medicine, Glycobiology Research and Training Center, and.
authors.forename: Shoib S
authors.initials: SS
authors.lastname: Siddiqui
authors.affiliation: Departments of Medicine and Cellular and Molecular Medicine, Glycobiology Research and Training Center, and.
authors.forename: Lingquan
authors.initials: L
authors.lastname: Deng
authors.affiliation: Departments of Medicine and Cellular and Molecular Medicine, Glycobiology Research and Training Center, and.
authors.forename: Michal A
authors.initials: MA
authors.lastname: Stanczak
authors.affiliation: Departments of Medicine and Cellular and Molecular Medicine, Glycobiology Research and Training Center, and.
authors.forename: Liwen
authors.initials: L
authors.lastname: Deng
authors.affiliation: Departments of Medicine and Cellular and Molecular Medicine, Glycobiology Research and Training Center, and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Verhagen
authors.affiliation: Departments of Medicine and Cellular and Molecular Medicine, Glycobiology Research and Training Center, and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Secrest
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201.
authors.forename: Chrissy
authors.initials: C
authors.lastname: Lusk
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201.
authors.forename: Ann G
authors.initials: AG
authors.lastname: Schwartz
authors.affiliation: Departments of Medicine and Cellular and Molecular Medicine, Glycobiology Research and Training Center, and.
authors.forename: Nissi M
authors.initials: NM
authors.lastname: Varki
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA 92093; and.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Bui
authors.affiliation: Departments of Medicine and Cellular and Molecular Medicine, Glycobiology Research and Training Center, and a1varki@ucsd.edu.
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D008024:Ligands; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology; D009369:Neoplasms / Q000276:immunology*; D018375:Neutrophil Activation; D020641:Polymorphism, Single Nucleotide; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D008024:Ligands; C412227:SIGLEC9 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C422908:Siglece protein, mouse
keywords: hypersialylation; immune evasion; tumor-associated inflammation; tumor-associated macrophages; tumor-associated neutrophils