A Current Viewpoint of Lymphangioleiomyomatosis Supporting Immunotherapeutic Treatment Options

Abstract

Lymphangioleiomyomatosis (LAM) leads to hyperproliferation of abnormal smooth muscle cells in the lungs, associated with diffuse pulmonary parenchymal cyst formation and progressive dyspnea on exertion. The disease targets women of child-bearing age. Complications include pneumothoraces and chylous pleural effusions. Ten-year survival is estimated at 70%, and lung transplantation remains the only validated treatment. It has been observed that LAM cells express markers associated with melanocytic differentiation, including gp100 and MART-1. Other melanocytic markers have also been observed. The same proteins are targeted by T cells infiltrating melanoma tumors as well as by T cells infiltrating autoimmune vitiligo skin, and these antigens are regarded as relatively immunogenic. Consequently, vaccines have been developed for melanoma targeting these and other immunogenic melanocyte differentiation proteins. Preliminary data showing susceptibility of LAM cells to melanoma derived T cells suggest that vaccines targeting melanosomal antigens can be successful in treating LAM.

Antibody αPEP13h Reacts With Lymphangioleiomyomatosis Cells in Lung Nodules

“…39 Interestingly, the lysosomal and membrane-associated protein tetraspanin CD63, or LAMP3, 26 is highly expressed in LAM cells. Although other melanosomal proteins have been investigated in LAM cells, the results appear more variable for proteins such as tyrosinase and tyrosinase-associated protein.…”

“…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.…”

Adolescent form of sporadic lymphangioleiomyomatosis (S-LAM)

“…The pathogenesis of LAM also comprises LAM-cell propagation through lymphatic channels, secretion of two lymphangiogenic growth factors: VEGF-D (vascular endothelial growth factor D) and VEGF-C (vascular endothelial growth factor C) by LAM cells, 4 oestrogen (through interaction with signalling events in LAM cells), and altered metabolism of extracellular matrix. 5,6 …”

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

“…1-5) explore the translational hypothesis about immunotherapeutic options in LAM focusing on potential benefits of melanosomal antigens (7). The melanocytic cell markers have been identified in LAM.…”

“…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).…”