Positioning Ganglioside D3 as an Immunotherapeutic Target in Lymphangioleiomyomatosis Journal Article

Authors: Gilbert, E. R.; Eby, J. M.; Hammer, A. M.; Klarquist, J. S.; Christensen, D. G.; Barfuss, A. J.; Boissy, R. E.; Picken, M. M.; Love, R. B.; Dilling, D. F.; Le Poole, I. C.
Article 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.
Journal Title: The American journal of pathology
Volume: 183
Issue: 1
ISSN: 1525-2191; 0002-9440
Publisher: Elsevier Inc  
Date Published: 2013
Start Page: 226
End Page: 234
Language: ENG
Notes: LR: 20131211; CI: Copyright (c) 2013; JID: 0370502; 0 (Antigens, CD1d); 0 (Gangliosides); 0 (Tumor Markers, Biological); 62010-37-1 (ganglioside, GD3); EIN: Am J Pathol. 2013 Nov;183(5):1698; 2012/07/31 [received]; 2013/02/19 [revised]; 2013/04/01 [accepted]; 2013/05/10 [aheadofprint]; ppublish
LUC Authors
  1. Daniel Dilling
    34 Dilling
  2. Maria M. Picken
    55 Picken
  3. Isabelle Caroline LePoole
    19 LePoole
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