Melanoma-associated antigen expression in lymphangioleiomyomatosis renders tumor cells susceptible to cytotoxic T cells. Am J Pathol 2009 Dec;175(6):2463-72
Date
11/07/2009Pubmed ID
19893037Pubmed Central ID
PMC2789635DOI
10.2353/ajpath.2009.090525Scopus ID
2-s2.0-73549088735 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
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.
Author List
Klarquist J, Barfuss A, Kandala S, Reust MJ, Braun RK, Hu J, Dilling DF, McKee MD, Boissy RE, Love RB, Nishimura MI, Le Poole ICMESH terms used to index this publication - Major topics in bold
Antigens, NeoplasmCell Separation
Cytotoxicity, Immunologic
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Humans
Immunohistochemistry
Immunotherapy
Intramolecular Oxidoreductases
Lymphangioleiomyomatosis
Lymphocytes, Tumor-Infiltrating
MART-1 Antigen
Melanoma
Membrane Glycoproteins
Microscopy, Electron, Transmission
Neoplasm Proteins
Oxidoreductases
Skin Neoplasms
T-Lymphocytes, Cytotoxic
gp100 Melanoma Antigen
