Positioning ganglioside D3 as an immunotherapeutic target in lymphangioleiomyomatosis.

[lymphangioleiomyomatosis]

Tumors that develop in lymphangioleiomyomatosis (LAM ) as a consequence of biallelic loss of TSC 1 or TSC 2 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 D 3 (GD 3 ) in LAM . GD 3 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 GD 3 , which may allow for a population of GD 3 -expressing LAM cells to expand within patients . This is supported by the demonstrated sensitivity of cultured LAM cells to complement mediated cytotoxicity via GD 3 antibodies . GD 3 can serve as a natural killer T (NKT ) cell antigen when presented on CD 1 d molecules expressed on professional antigen-presenting cells . Although CD 1 d-expressing monocyte derivatives were present in situ , enhanced NKT-cell recruitment to LAM lung was not observed . Cultured LAM cells retained surface expression of GD 3 over several passages and also expressed CD 1 d , implying that infiltrating NKT cells can be directly cytotoxic toward LAM lung lesions . Immunization with antibodies to GD 3 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 GD 3 as a suitable target for immunotherapy of LAM .