title: Melanoma-associated antigen expression in lymphangioleiomyomatosis renders tumor cells susceptible to cytotoxic T cells.
abstract: The antibody HMB45 is used to diagnose lymphangioleiomyomatosis, a hyperproliferative disorder of lung smooth muscle cells with mutations in both alleles of either TSC1 or TSC2. A subset of these tumor cells expresses the melanoma-associated antigens gp100 and melanoma antigen recognized by T cells (MART-1). To explore the feasibility of targeting tumors in lymphangioleiomyomatosis by melanoma immunotherapy, we therefore assessed melanoma target antigen expression and existing immune infiltration of affected tissue compared with normal lung and melanoma as well as the susceptibility of cultured lymphangioleiomyomatosis cells to melanoma reactive cytotoxic T lymphocytes in vitro. Tumors expressed tyrosinase-related proteins 1 and 2 but not tyrosinase, in addition to gp100 and MART-1, and were densely infiltrated by macrophages, but not dendritic cells or T cell subsets. Although CD8(+) lymphocytes were sparse compared with melanoma, cells cultured from lymphangioleiomyomatosis tissue were susceptible to cytotoxic, gp100 reactive, and major histocompatibility complex class I restricted CD8(+) T cells in functional assays. Responder T cells selectively clustered and secreted interferon-gamma in response to HLA-matched melanocytes and cultured lymphangioleiomyomatosis cells. This reactivity exceeded that based on detectable gp100 expression; thus, tumor cells in lymphangioleiomyomatosis may process melanosomal antigens different from melanocytic cells. Therefore, boosting immune responses to gp100 in lymphangioleiomyomatosis may offer a highly desirable treatment option for this condition.
authors.affiliation: Oncology Institute, Loyola University, Chicago, Illinois 60153, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Klarquist
authors.forename: Allison
authors.initials: A
authors.lastname: Barfuss
authors.forename: Sridhar
authors.initials: S
authors.lastname: Kandala
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Reust
authors.forename: Ruedi K
authors.initials: RK
authors.lastname: Braun
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hu
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Dilling
authors.forename: Mark D
authors.initials: MD
authors.lastname: McKee
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Boissy
authors.forename: Robert B
authors.initials: RB
authors.lastname: Love
authors.forename: Michael I
authors.initials: MI
authors.lastname: Nishimura
authors.forename: I Caroline
authors.initials: IC
authors.lastname: Le Poole
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D019746:Intramolecular Oxidoreductases / Q000276:immunology / Q000378:metabolism; D018192:Lymphangioleiomyomatosis / Q000276:immunology* / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D009363:Neoplasm Proteins / Q000276:immunology* / Q000378:metabolism; D010088:Oxidoreductases / Q000276:immunology / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D058951:gp100 Melanoma Antigen
chemical_list: D000951:Antigens, Neoplasm; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D058951:gp100 Melanoma Antigen; D010088:Oxidoreductases; C064056:tyrosinase-related protein-1; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase