Abstract 2893: Inhibition of ADAMTS4 and 5 to regulate the tumor microenvironment

Abstract Background: Triple-negative breast cancer accounts for approximately 10~15% of all breast cancers and is characterized by the absence of ER, PR, and HER2 receptors, making targeted therapies challenging due to the lack of biomarkers. ADAMTSs (ADAM metallopeptidase with thrombospondin) are complex extracellular proteases known for their roles in facilitating cancer cell proliferation and safeguarding tumor functions. This enzyme is secreted by cancer cells and various immune cells, influencing the tumor microenvironment. ADAMTSs modulate cellular adhesion, migration, proliferation, and vascular development by cleaving components of the extracellular matrix and regulatory factors such as chemokines and cytokines. Our aim is to positively manipulate the tumor microenvironment of triple-negative breast cancer by inhibiting ADAMTSs, presenting a new strategy for treating this challenging type of breast cancer that lacks targeted therapeutic options. Results: To confirm the anticancer effects of a protease inhibitor concurrently targeting ADAMTS4 and 5, a co-culture of triple-negative breast cancer cells (MDA-MB-157) and THP-1 was established to artificially create a tumor microenvironment. Subsequently, a wound healing assay was conducted, revealing that treatment with the ADAMTS4 and 5 dual inhibitor effectively inhibited cancer cell migration. This observed anticancer effect is attributed to the inhibition of CXCL16 secretion by the ADAMTS4 and 5 dual inhibitor. To verify the anti-tumor mechanisms of ADAMTS4 and 5, MDA-MB-157 cells, a triple-negative breast cancer cell line, were treated with IFNγ and TNFα to promote CXCL16 secretion artificially. Upon treatment with varying concentrations of the ADAMTS4, 5 dual inhibitor, it was confirmed that the secretion of CXCL16 was inhibited in a dose-dependent manner. In a mouse model with transplanted 4T1 breast cancer cells, treatment with the ADAMTS4, 5 dual inhibitor resulted in the suppression of CXCL16 secretion, leading to an increase in M1 macrophages. Additionally, it was observed that the inhibitor induced CD8+ T cell activation. These regulation and changes of immune cells through inhibition of ADAMTS4 and 5 control the TME to resist tumor cells. Conclusion: ADAMTSs are known as protein-degrading enzymes responsible for the degradation, modification, and regulation of proteins. Recent research has revealed that ADAMTSs play a crucial role in the proliferation and survival of cancer. Activation of ADAMTS4 and 5 has been shown to promote the secretion of CXCL16, leading to the differentiation of macrophages into tumor-associated macrophages. Specifically, ADAMTS4 and 5 convert membrane-bound CXCL16 into a soluble form, exacerbating the tumor microenvironment of triple-negative breast cancer. Therefore, inhibiting ADAM4, 5 is intended to change or maintain TME in a suitable state for anti-cancer therapy, which could lead to a new strategy for anti-cancer therapy. Citation Format: Cham han Lee, Seong Keun Kim, Sung Moo Kim, Young Sang Kim, Sang Hyeob Lee, Seong Yun Ha, Yun Sun Lee, Jin Yi Yang. Inhibition of ADAMTS4 and 5 to regulate the tumor microenvironment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2893.