Blocking secretion of exosomes by GW4869 dampens CD8+ T cell exhaustion and prostate cancer progression

Abstract

Functional exhaustion of T lymphocytes is considered an important factor in the failure of tumor treatment. Accumulating evidence has shown that tumor cells cultivate their immune microenvironment through secreting exosomes. However, the mechanism through which tumor cell-derived exosomes participate in the regulation of lymphocyte function remains unclear. In this study, we found that exosomes derived from prostate cancer (PCa) cells were able to upregulate the expression of PD-1 and TIM-3 in CD8+ T cells, inducing the secretion of cytokines related to T cell exhaustion and significantly decreasing the ability to kill PCa cells. Importantly, our data indicated that treatment with GW4869 could reverse the effects of PCa-derived exosomes on CD8+ T cells and further inhibit the growth of PCa cells in vivo and in vitro by blocking the generation of exosomes. Our findings support the notion that exosomes derived from PCa cells can induce T cell exhaustion and promote PCa progression, while treatment of GW4869 effectively rejuvenates CD8+ T cells and reverses the effect of PCa exosomes. These findings indicate that GW4869 has potential in the treatment of PCa.