Abstract 2952: The novel cathepsin L/K inhibitors KGP94 and KGP207 prevent M0 to M2 macrophage differentiation and macrophage-mediated pro-tumor functions

Abstract

Abstract Tumor-associated macrophages play many important roles in tumor progression, including facilitating tumor cell invasion and angiogenesis. Due to their numerous pro-tumor functions, tumor-associated macrophages represent an important cell population in the design of targeted anti-cancer therapies. Interleukin-4-mediated activation of macrophages resulted in an M2-like, or pro-tumor macrophage phenotype, often associated with increased expression of proteases including the lysosomal cathepsin L. Cathepsin L is important in both macrophage and tumor cell invasion, whereby secreted cathepsin L degrades the extracellular matrix, allowing for cell infiltration. The present study examined the role of cathepsin L in M0 to M2 differentiation and macrophage-mediated tumor cell invasion using the novel cathepsin L/K inhibitors KGP94 and KGP207 [Dr. Kevin Pinney, Baylor University]. KGP94 and KGP207 prevented M2 macrophage motility and invasion in in vitro migration and invasion assays. Moreover, KGP94 and KGP207 reduced macrophage-stimulated invasion of 4T1 murine breast cancer cells. Together, these data suggested that cathepsin L was necessary for macrophage invasion and motility and for macrophage-mediated invasion of breast cancer cells. KGP94 and KGP207 treatment partially prevented IL-4-stimulated M0 to M2 differentiation of macrophages as determined by a decrease in the IL-4-induced expression of the M2 marker Arginase-1 upon drug treatment. Additionally, exogenous recombinant cathepsin L partially stimulated the expression of Arginase-1 in M0 macrophages. Together, these data suggest that cathepsin L plays a role in macrophage M0 to M2 differentiation. In conclusion, the novel cathepsin L/K inhibitors KGP94 and KGP207 prevented M0 to M2 differentiation, macrophage invasion, and macrophage-stimulated invasion of breast cancer cells. These data highlight the importance of cathepsin L in macrophage functions and suggest that cathepsin L inhibition is a viable approach for the treatment of tumors associated with high macrophage infiltration. Citation Format: Samantha S. Dykes, Dietmar W. Siemann. The novel cathepsin L/K inhibitors KGP94 and KGP207 prevent M0 to M2 macrophage differentiation and macrophage-mediated pro-tumor functions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2952. doi:10.1158/1538-7445.AM2017-2952