title: Tumor-derived chemokine CCL5 enhances TGF-β-mediated killing of CD8(+) T cells in colon cancer by T-regulatory cells.
abstract: Chemokine CCL5/RANTES is highly expressed in cancer where it contributes to inflammation and malignant progression. In this study, we show that CCL5 plays a critical role in immune escape in colorectal cancer. We found that higher levels of CCL5 expression in human and murine colon tumor cells correlated with higher levels of apoptosis of CD8+ T cells and infiltration of T-regulatory cells (T(reg)). In mouse cells, RNA interference (RNAi)-mediated knockdown of CCL5 delayed tumor growth in immunocompetent syngeneic hosts but had no effect on tumor growth in immunodeficient hosts. Reduced tumor growth was correlated with a reduction in T(reg) infiltration and CD8(+) T-cell apoptosis in tumors. Notably, we found that CCL5 enhanced the cytotoxicity of T(reg) against CD8(+) T cells. We also found tumor growth to be diminished in mice lacking CCR5, a CCL5 receptor, where a similar decrease in both T(reg) cell infiltration and CD8(+) T-cell apoptosis was noted. 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-deficient T(reg) or to enhance their cytotoxic effects against CD8(+) T cells. CCR5 signaling blockade also diminished the in vivo suppressive capacity of T(reg) in inhibiting the antitumor responses of CD8(+) T cells, in the same way as CCL5 signaling blockade. Together, our findings establish that CCL5/CCR5 signaling recruits T(reg) to tumors and enhances their ability to kill antitumor CD8(+) T cells, thereby defining a novel mechanism of immune escape in colorectal cancer.
authors.affiliation: Graduate Institute of Biomedical Sciences, Chang Gung University, Taiwan.
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Chang
authors.forename: Yung-Chang
authors.initials: YC
authors.lastname: Lin
authors.forename: Jayashri
authors.initials: J
authors.lastname: Mahalingam
authors.forename: Ching-Tai
authors.initials: CT
authors.lastname: Huang
authors.forename: Ten-Wen
authors.initials: TW
authors.lastname: Chen
authors.forename: Chiao-Wen
authors.initials: CW
authors.lastname: Kang
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Peng
authors.forename: Yu-Yi
authors.initials: YY
authors.lastname: Chu
authors.forename: Jy-Ming
authors.initials: JM
authors.lastname: Chiang
authors.forename: Avijit
authors.initials: A
authors.lastname: Dutta
authors.forename: Yuan-Ji
authors.initials: YJ
authors.lastname: Day
authors.forename: Tse-Ching
authors.initials: TC
authors.lastname: Chen
authors.forename: Chau-Ting
authors.initials: CT
authors.lastname: Yeh
authors.forename: Chun-Yen
authors.initials: CY
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D055785:Gene Knockdown Techniques; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D018946:Chemokine CCL5; D019713:Receptors, CCR5; D016212:Transforming Growth Factor beta