LRP2 expression in melanoma is associated with a transitory cell state, increased T cell infiltration, and is upregulated by IFNγ signaling

Low density lipoprotein receptor-related protein 2 (LRP2) is a 600 kilodalton multi-ligand endocytic membrane receptor expressed in several cell types during fetal development, including neuroepithelial cells, and in select absorptive epithelial cells in the adult. In epithelial cancers, LRP2 expression is associated with a differentiated tumor cell state and better prognosis. In previous work, we found that while LRP2 is not expressed in benign naevi, it is frequently acquired in melanoma. However, the molecular drivers of LRP2 expression in melanoma and characteristics of LRP2-expressing melanoma have yet to be described. Here, we show that LRP2 expression is related to a transitory melanoma cell state defined by co-expression of melanocyte lineage and neural crest transcriptional programs. Further, we reveal that melanoma LRP2 expression is increased in T cell-inflamed tumors, and is directly upregulated through interferon-gamma signaling. Correlation of melanoma LRP2 expression with clinicopathological variables demonstrates that LRP2 expression is associated with low Breslow thickness and low clinical stage in primary melanomas. Taken together, the present study describes the characteristics of LRP2-expressing melanoma and reveals interferon gamma signaling as a novel strong positive regulator of LRP2 expression in melanoma. SignificanceMelanoma cells often acquire LRP2 expression but the drivers of LRP2 expression in this setting and characteristics of LRP2-expressing melanoma remain unclear. Here, we show that LRP2 expression is related to a transitory melanoma differentiation cell state. Further, LRP2 expression in melanoma correlates with a T cell-inflamed tumor microenvironment and LRP2 expression in melanoma cells can be directly increased by interferon-gamma. In addition, LRP2 expression is associated with less advanced histopathological characteristics of melanoma. These findings encourage future studies on LRP2 in settings with increased interferon signaling, in particular in melanoma metastases following immunotherapy.