Tspan6 stimulates the chemoattractive potential of breast cancer cells for B cells in an EV- and LXR-dependent manner

• Published in: Cell reports (Cambridge) Vol. 42; no. 3; p. 112207
• Main Authors: Molostvov, Guerman, Gachechiladze, Mariam, Shaaban, Abeer M., Hayward, Steven, Dean, Isaac, Dias, Irundika H.K., Badr, Nahla, Danial, Irini, Mohammed, Fiyaz, Novitskaya, Vera, Paniushkina, Liliia, Speirs, Valerie, Hanby, Andrew, Nazarenko, Irina, Withers, David R., van Laere, Steven, Long, Heather M., Berditchevski, Fedor
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28-03-2023; Elsevier
• Subjects: B cells; B-Lymphocytes - metabolism; breast cancer; Breast Neoplasms - genetics; CP: Cancer; Female; Humans; Liver X Receptors - metabolism; LXR; oxysterols; Oxysterols - pharmacology; Tetraspanins; Tumor Microenvironment; tetraspanins; oxysterols; CP: Cancer; LXR; breast cancer; B cells; tumor microenvironment
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112207

The immune microenvironment in breast cancer (BCa) is controlled by a complex network of communication between various cell types. Here, we find that recruitment of B lymphocytes to BCa tissues is controlled via mechanisms associated with cancer cell-derived extracellular vesicles (CCD-EVs). Gene expression profiling identifies the Liver X receptor (LXR)-dependent transcriptional network as a key pathway that controls both CCD-EVs-induced migration of B cells and accumulation of B cells in BCa tissues. The increased accumulation oxysterol ligands for LXR (i.e., 25-hydroxycholesterol and 27-hydroxycholesterol) in CCD-EVs is regulated by the tetraspanin 6 (Tspan6). Tspan6 stimulates the chemoattractive potential of BCa cells for B cells in an EV- and LXR-dependent manner. These results demonstrate that tetraspanins control intercellular trafficking of oxysterols via CCD-EVs. Furthermore, tetraspanin-dependent changes in the oxysterol composition of CCD-EVs and the LXR signaling axis play a key role in specific changes in the tumor immune microenvironment.
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•Tspan6 regulates recruitment of B cells to the tumor microenvironment•Tspan6 controls migration of B cells by cell-derived extracellular vesicles (EVs)•Tspan6 facilitates accumulation of hydroxycholesterols in EVs•Migration of B cells involves activation of LXR-dependent pathway
B lymphocytes play an important role in anti-cancer immunity. Molostvov et al. demonstrate that migration and recruitment of B cells to breast cancer tissues are controlled by Tspan6 expression on cancerous cells. The underlying mechanisms involve increased accumulation of hydroxycholesterols on cell-derived extracellular vesicles and activation of the LXR pathway.