| Summary: | 博士 === 長庚大學 === 生物醫學研究所 === 100 === Our lab has shown that CD103+effector/memory Treg cells are potent suppressors in control of anti-tumor responses. However, the underlying mechanisms for this potent suppression ability remain unclear. Herein, I investigated this issue by using mouse CT26 colon tumor model. Firstly, CD103+ Treg cells expressed significantly higher levels of CCR5 and accumulated more in tumor microenvironment than CD103- Treg cells. On the other hand, I found that higher expression levels of CCR5-related ligand CCL5 in human and mouse colon tumor cells and correlated with higher levels of apoptosis of CD8+ T cells and infiltration of effector/memory Treg cells, Furthermore, RNA interference-mediated knockdown of CCL5 in tumor cells delayed tumor growth in immunocompetent syngeneic hosts but not in immunodeficient hosts. Reduced tumor growth was correlated with a reduction in CD103+ Treg infiltration and CD8+ T cell apoptosis in tumors microenvironment. Notably, I found that CCL5 enhanced the killing ability of Treg cells against CD8+ T cells through TGF-β production. TGF-β signaling blockade diminished apoptosis of CD8+ T cells, implicating TGF-β as an effector of CCL5 action. In support of this concept, CCL5 failed to enhance the production of TGF-β by CCR5-/- Treg cells or to enhance their killing ability against CD8+ T cells. Finally, a blockade of CCR5 signaling impairs in vivo suppression ability of CD103+ Treg cells against anti-tumor responses. Together, my findings establish that CCL5/CCR5 signaling recruits effector/memory Treg cells to tumors and enhances their ability to kill antitumor CD8+ T cells, thereby defining a novel mechanism of immune escape in tumor development.
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