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-␥ 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.

LAM cells biology and lymphangioleiomyomatosis

“…Further studies confirmed the immunoreactivity of these structures with the HMB-45 antibody [22]. Some of the LAM cells also express a small transmembrane protein, melanoma-associated antigen recognized by T cells (MART-1), which is widely expressed in melanoma cells [23]. Both gp100 and MART-1 can be recognized by T cells, increasing the susceptibility of these cells to the cytotoxic activity of T cells.…”

“…This feature may become an important therapeutic target. Expression of tyrosinase-related proteins TRP-1 (gp-75) and TRP-2 was also observed in LAM cells [23]. Other markers of melanoma, such as CD63, a protein belonging to the tetraspanin family, or a recently described unknown protein which reacts with PNL2 antibody, are also present in LAM cells [24].…”

Antibody αPEP13h Reacts With Lymphangioleiomyomatosis Cells in Lung Nodules

“…Although other melanosomal proteins have been investigated in LAM cells, the results appear more variable for proteins such as tyrosinase and tyrosinase-associated protein. 39,40 In addition, antimelanosomal-specifi c antibodies, or PNL2, 26 react with a large number of LAM lung nodules. However, LAM cells are more defi nitively identifi ed for their reactivity to HMB-45 and now a PEP13h.…”

Treatment Option(s) for Pulmonary Lymphangioleiomyomatosis: Progress and Current Challenges

“…Using tissue samples from subjects with LAM, the authors identified the expression of tyrosinase-related proteins (TRPs) 1 and 2 involved in melanogenesis in LAM samples in comparison to normal lung. Interestingly, the LAM nodules were densely infiltrated by macrophages but not dendritic cells or T cell subsets, demonstrating that LAM cell growth was not accompanied by enhanced immune infiltration (6). Further, cells dissociated from the LAM lung were susceptible to cytotoxic, gp100-reactive, and major histocompatibility complex class I restricted CD8 1 T cells, suggesting that immunotargeting gp100 provides beneficial cytotoxic effects on LAM cell growth.…”

“…SM-like LAM cells show high immunoreactivity for PCNA (proliferating cell nuclear antigen), a marker of DNA synthesis and cell proliferation, compared with the epithelioidlike HMB45-positive cells (2), suggesting that SM-like LAM cells represent the proliferative component of the LAM nodules. The role of melanocyte-specific markers in LAM and whether they could be targeted therapeutically have been explored (6) and were reviewed in the January issue (7).…”