Spatial Profiling Shows That Lymphatic Endothelial Cells Form the Core of Kaposi Sarcoma (KS)

The lineage of the Kaposi sarcoma (KS) tumor cell remains elusive, limiting opportunities for targeted therapy. We performed concurrent spatial imaging of 5 bona fide lymphatic endothelial cell markers together with the KS herpesvirus viral protein latency-associated nuclear antigen (LANA) in 30 well-characterized HIV-positive KS biopsies (n = 1,740,744 cells). Nodular KS lesions showed significantly more circular nuclei than plaque KS, indicating distinct cellular morphologies. Both forms contained dense areas of LANA-positive cells-termed "LANA nests." Among the endothelial cell markers, vascular endothelial growth factor receptor 3 was most abundantly expressed, although many vascular endothelial growth factor receptor 3-positive cells were LANA negative. Podoplanin and LYVE-1 consistently colocalized with each other, whereas CD31 and VE-Cadherin were variably expressed within and across lesions. Together, these observations reveal that KS lesions are composed of multiple microenvironments: LANA-dense nests, LANA-sparse fascicles, and mature lymphatic or blood vessels, some of which also harbored LANA-positive lining cells. At present, targeted therapies do not account for this variability; generally, responses are not based on pathology. Spatial changes in the tumor microenvironment that may provide insights into drug action and resistance mechanisms are missed.