LSECtin on tumor-associated macrophages enhances breast cancer stemness via interaction with its receptor BTN3A3

Abstract

Macrophages have been suggested to contribute to constructing a cancer stem cell (CSC) niche. However, whether and how macrophages regulate the activity of CSCs through juxtacrine signaling are poorly understood. Here we report LSECtin, a transmembrane protein highly expressed on tumor-associated macrophages (TAMs), enhances stemness of breast cancer cells (BCCs). We identified BTN3A3, a B7 family member with previously unknown functions as the receptor for LSECtin on BCCs responsible for stemness-promoting effect of LSECtin. In mice bearing human tumor xenografts, either macrophage-specific ablation of LSECtin or silencing of BTN3A3 in BCCs decreased CSC frequency and tumor growth. Admixture of LSECtin-positive macrophages increased the tumorigenic activity of BCCs dependent on BTN3A3. Disruption of the LSECtin-BTN3A3 axis with BTN3A3-Fc or anti-BTN3A3 mAb has a therapeutic effect on breast cancer. These findings define a juxtacrine signaling mechanism by which TAMs promote cancer stemness. Targeting this axis in the CSC niche may provide potential therapies to breast cancer.

Cancer Stemness Meets Immunity: From Mechanism to Therapy

“…Finally, in addition to soluble factors, TAMs can promote CSC stemness via direct interactions. Specifically, in breast cancer, liver, and lymph node sinusoidal endothelial cell C-type, lectin is a transmembrane protein highly expressed on TAMs that interacts with butyrophilin subfamily 3 member A3 receptor on cancer cells to enhance stemness ( Liu et al, 2019 ).…”

Molecular Recognition in C‐Type Lectins: The Cases of DC‐SIGN, Langerin, MGL, and L‐Sectin

“…The coregulatory molecule LAG‐3 on T‐cells was identified as its binding partner [257] . Moreover, LSECtin has also been found to be involved in tumor progression in breast cancer [258] . Specifically, it is highly expressed by tumor‐associated macrophages in human breast cancer tissue, where it is able to interact with the breast cancer cell‐intrinsic BTN3A3 receptor to promote tumor stemness.…”

The Tumor Microenvironment as a Driving Force of Breast Cancer Stem Cell Plasticity

“…It is therefore likely that macrophages can promote cancer stemness and metastasis also through the secretion of IL-1β. TAMs may also potentiate BC stemness via cell-cell interactions with CSCs: they express LSECtin, a transmembrane protein that interacts with the butyrofilin family molecule BTN3A3 in tumor cells, enhancing their stemness features both in vitro and in vivo [ 60 ].…”