Abstract 4932: Kaposi's sarcoma represents a dynamic pathogenic process involving ongoing macrophage replenishment with both tumor cells as well as macrophages expressing CD206, a target for the recently approved imaging agent, Tilmanocept
Authors: McGrath Michael S. , Bracci Paige M. , Cope Frederick O. , Zhang Rongzhen 
Published: May 2015

Abstract
Introduction
In patients with Kaposi's sarcoma (KS), plasma elevation of macrophage (MO)-produced growth factors such as EGF and bFGF suggests a role for tumor associated MOs (TAM) in KS pathogenesis. Goals of the current study were twofold: 1) To define MO subsets using M1 (MAC387), M2 (CD163, CD206) and pan macrophage CD68 antibodies in tissue microarray (TMA) analysis of all forms of KS including plaque, oral and visceral tumors. 2) To test whether CD206, the macrophage mannose receptor recognized by the recently approved imaging agent Tilmanocept (Navidea), is present on TAMs and KS tumor cells. If TAMs and KS tumor cells are CD206+, Tilmanocept could allow KS specific imaging for purposes of tumor staging, a procedure heretofore unapproachable.
Methods
A KS TMA with 66 KS cases and controls was obtained from the AIDS and Cancer Specimen Resource (ACSR). MO antigens were identified by IHC studies and results were standardized to the proportion of KSHV LANA+ cells (KS tumor specific marker). ACSR KS specimens from Kenya and South Africa (where KS is a common cause of death) were tested in a follow-up study.
Results
Most TAMs in KS tissues were identified with the M2 specific anti-CD163 antibody whereas the M1 anti-MAC387 antibody identified a smaller subset of cells. The CD68 antibody also identified a large number of TAMs in more than 90% of tumors. KS tumor spindle cells in general expressed macrophage antigens; however the most prevalent antigen for both KS tumor cells (LANA+) and TAMs was CD206 molecule. Expression of MO antigens and CD206 in relation to level of LANA within tumor tissues was similar across all tissue forms of KS (plaque, oral, visceral). In general, KS tissues from Africa contained higher relative levels of TAMs than tissues from US cases.
Conclusions
KS pathogenesis appears to involve an ongoing replenishment of TAMs from recent blood derived monocytes that express either M1 (MAC-387) or M2 (CD163) antigens. Both MO antigens identify cells that are turned over within days, suggesting that KS while appearing relatively indolent has a very dynamic MO migration component, apparently required for KS pathogenesis. This study also confirmed a preliminary study (Uccini et al. AJP 1997) that found both TAMs and KS tumor cells to express the CD206 macrophage mannose receptor. Tilmanocept, a technetium labeled ligand for CD206 recently approved by the FDA for human imaging use, may allow effective imaging of KS involved nodes and other visceral sites of disease. Considering the current inability of clinicians to determine the degree of KS spread beyond the presence of obvious skin lesions, the potential for using Tilmanocept to define tumor burden may allow earlier tumor specific treatment beyond the current use of anti-retroviral therapy alone which is proving ineffective in growing numbers of KS patients worldwide.
Citation Format: Michael S. McGrath, Paige M. Bracci, Frederick O. Cope, Rongzhen Zhang. Kaposi's sarcoma represents a dynamic pathogenic process involving ongoing macrophage replenishment with both tumor cells as well as macrophages expressing CD206, a target for the recently approved imaging agent, Tilmanocept. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4932. doi:10.1158/1538-7445.AM2014-4932