Expression of Melanocyte Differentiation Markers in Pulmonary Lymphangioleiomyomatosis Offers Potential for Immunotheraputic Targeting.
Jared Klarquist, Raymond Boissy, Maria M Picken, Robert Love, Caroline Le Poole. Loyola University Medical Center, Maywood, IL
Background: Lymphangioleiomyomatosis (LAM), a hyperproliferative disorder of smooth muscle cells, involves formation of tumor nodules in the lungs in premenopausal women, following mutations in both alleles of TSC-1 or TSC-2. Tumor growth is slow, with a life expectancy of approximately 10 years at diagnosis. Although Rapamycin alleviates symptoms of LAM, it does not provide lasting disease remission and LAM is ultimately lethal unless salvage lung transplantation is performed. The detection of smooth muscle cells co-expressing HMB45 is diagnostic. However, a subset of LAM cells also express gp100 and a melanoma-associated antigen recognized by T cells (MART-1); melanosomal markers are also observed by electron microscopy (EM). Immunotherapy has been applied to treat patients with melanoma. This study aims to explore the feasibility of targeting tumors in LAM by melanoma immunotherapy.
Design: The presence and abundance of melanosomal markers gp100, MART-1, TRP-1, TRP-2, tyrosinase as well as GD3, a ganglioside widely expressed in human malignant melanoma cell lines and tumors, and immune infiltration were studied in cryosections of LAM and normal lung. Cultured LAM cells displaying early melanosomes by EM were subjected to Cytotoxic T Lymphocytes (CTL) and included in complememnt-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) assays using antibodies to GD3.
Results: Expression of gp100 was abundant and only superseded by TRP-1. In serial sections, expression of separate melanosomal markers was observed in different cells. Among CD4+ and CD8+ T cells, dendritic cells and macrophages, only macrophage infiltration was markedly increased in LAM. Remarkably, melanoma-derived, HLA-matched gp100 reactive CTL and autologous T cells from LAM lung reacted with cultured LAM cells. Also, antibodies to GD3 mediated CDC and ADCC responses.
Conclusions: Separate melanosomal markers are expressed in different LAM cells, with TRP-1 and gp100 being most abundant, and gp100-reactive CTL cells react with cultured LAM cells. Macrophage infiltration is markedly increased in LAM. These findings suggest that occult expression of immunogenic target molecules does elicit marked T cell responses and that targeting multiple antigens may be the strategy of choice for eradicating LAM tumors. Since LAM tumors are slow growing, use of immunotherapeutic strategies may be more successful than in melanomas which are rapidly progressing.
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 264, Wednesday Morning