title: Positioning ganglioside D3 as an immunotherapeutic target in lymphangioleiomyomatosis.
abstract: Tumors that develop in lymphangioleiomyomatosis (LAM) as a consequence of biallelic loss of TSC1 or TSC2 gene function express melanoma differentiation antigens. However, the percentage of LAM cells expressing these melanosomal antigens is limited. Here, we report the overexpression of ganglioside D3 (GD3) in LAM. GD3 is a tumor-associated antigen otherwise found in melanoma and neuroendocrine tumors; normal expression is largely restricted to neuronal cells in the brain. We also observed markedly reduced serum antibody titers to GD3, which may allow for a population of GD3-expressing LAM cells to expand within patients. This is supported by the demonstrated sensitivity of cultured LAM cells to complement mediated cytotoxicity via GD3 antibodies. GD3 can serve as a natural killer T (NKT) cell antigen when presented on CD1d molecules expressed on professional antigen-presenting cells. Although CD1d-expressing monocyte derivatives were present in situ, enhanced NKT-cell recruitment to LAM lung was not observed. Cultured LAM cells retained surface expression of GD3 over several passages and also expressed CD1d, implying that infiltrating NKT cells can be directly cytotoxic toward LAM lung lesions. Immunization with antibodies to GD3 may thus be therapeutic in LAM, and enhancement of existing NKT-cell infiltration may be effective to further improve antitumor responses. Overall, we hereby establish GD3 as a suitable target for immunotherapy of LAM.
authors.affiliation: Department of Medicine, Loyola University Stritch School of Medicine, Maywood, Illinois 60153, USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Gilbert
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Eby
authors.forename: Adam M
authors.initials: AM
authors.lastname: Hammer
authors.forename: Jared
authors.initials: J
authors.lastname: Klarquist
authors.forename: David G
authors.initials: DG
authors.lastname: Christensen
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Barfuss
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Boissy
authors.forename: Maria M
authors.initials: MM
authors.lastname: Picken
authors.forename: Robert B
authors.initials: RB
authors.lastname: Love
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Dilling
authors.forename: I Caroline
authors.initials: IC
authors.lastname: Le Poole
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005732:Gangliosides / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D055611:Natural Killer T-Cells / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D055610:Antigens, CD1d; D014408:Biomarkers, Tumor; D005732:Gangliosides; C026226:ganglioside, GD3