Summary 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.
We 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
- breast cancer
- tumor microenvironment