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.
|Number of pages||22|
|Early online date||3 Mar 2023|
|Publication status||Published - 28 Mar 2023|
Bibliographical noteCopyright © 2023. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Acknowledgments and Funding Information: The authors are grateful to Dr. O. Yoshie, Dr. E. Rubinstein, and Dr. S. Charrin for providing anti-tetraspanin mAbs. This work was supported by MRC grant (to F.B., A.M.S., and H.M.L.), the Inflammatory Breast Cancer Network UK (to F.B.), and Ministry of Higher Education and Research , Egypt (N.B.). A.M.S. is supported by the Birmingham CRUK Centre . I.H.K.D. acknowledges funding from Aston Medical School . F.M. is supported by Wellcome Trust grant 099266/Z/12/Z .
- B cells
- CP: Cancer
- breast cancer
- tumor microenvironment