# Sphingosine-1-phosphate promotes CD8 T cell exhaustion in breast cancer via exosomal transfer of TGFBR2

## TL;DR

Sphingosine-1-phosphate promotes CD8 T cell exhaustion in breast cancer by transferring TGFBR2 via exosomes, suggesting a new target for improving antitumor immunity.

## Contribution

This study reveals a novel mechanism by which S1P promotes immune suppression in breast cancer through exosomal transfer of TGFBR2.

## Key findings

- S1P-treated breast cancer cells release exosomes with increased TGFBR2, leading to CD8 T cell exhaustion.
- S1P activates S1P1 receptor and AKT-Rab27a axis to enhance exosome release and TGFBR2 stability.
- Exosomes from S1P-treated cells promote tumor growth and T cell exhaustion in vivo, while TGFBR2 silencing reverses this effect.

## Abstract

Sphingosine-1-phosphate (S1P) has been implicated in promoting breast cancer progression, but its role in fostering an immunosuppressive microenvironment remains largely unexplored. In our study, co-culturing CD8 T cells with S1P-treated MCF7 cells significantly reduced CD8 T cell proliferation, an effect reversed by inhibiting exosome biogenesis. S1P treatment enhanced exosome release from breast cancer cells, with increased levels of TGFBR2 detected on the exosome surface. These S1P-induced exosomes promoted CD8 T cell exhaustion. Silencing TGFBR2 in cancer cells or treating with anti-TGFBR2 antibodies mitigated CD8 T cell exhaustion thereby highlighting the pivotal role of TGFBR2. Further investigation revealed that S1P drives the production of TGFBR2-loaded exosomes by activating the S1P1 receptor and engaging the AKT-Rab27a axis to facilitate exosome release. Additionally, S1P upregulates TGFBR2 expression and stability through the S1P1-LEF1 and S1P1-CREB1-USP8 pathways respectively, thereby contributing to immune suppression. In vivo administration of exosomes derived from S1P-treated murine breast cancer cells in a breast cancer allograft model markedly promoted tumor growth and heightened CD8 T cell exhaustion, whereas exosomes from TGFBR2-silenced, S1P-treated cells exerted the reverse effect, underscoring the pivotal role of the S1P-TGFBR2 axis in modulating the tumor microenvironment. These findings suggest that targeting the S1P-TGFBR2 pathway could enhance antitumor immunity in breast cancer.