title: Aberrant expression of chemokine receptor CCR4 in human gastric cancer contributes to tumor-induced immunosuppression.
abstract: The chemokine receptor CCR4 is preferentially expressed on certain immune cells and some hematological tumor cells, which play pivotal roles in suppression of host immune response. However, the reasons for the upmodulation of CCR4 and its immune functions in solid tumors remain unclear. Herein, we aimed to determine the expression profiles of CCR4 in gastric cancer cells and its role in regulating antitumor immunity. CCR4 expression was assessed in 63 cases of gastric carcinomas by immunohistochemistry. We found cancer cells in lymphocyte-rich carcinomas more frequently showed moderate to strong positive staining for CCR4 than those in conventional carcinomas (P = 0.041), and also found a positive relationship between expression of CCR4 and tumor necrosis factor-α (P = 0.012). Stimulation of gastric cell lines with various cytokines showed that tumor necrosis factor-α uniquely upmodulated CCR4 expression through activation of nuclear factor-κB. Additional coculture experiments showed the forced expression of CCR4 in SGC-7901 cells caused a significant reduction of γ-interferon and elevation of interleukin-10 secretion in the supernatants from cocultured SGC-7901 cells and PBMCs. In addition, granzyme A production in cancer cell-cocultured CD56(+) natural killer cells was significantly downregulated. Inhibition of the overexpressed CCR4 in cancer cells by an inhibitor of CCR4, compound 39, proved to partly restore the antitumor immunity in respect of the inverse changes in those factors. Our studies suggest that the aberrant expression of CCR4 in human gastric cancer could contribute to tumor-induced immunosuppression. Conceivably, downmodulation of CCR4 expression could be a promising immunotherapy for human gastric cancer.
authors: Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, China.
authors: Yong-Mei
authors: YM
authors: Yang
authors: A-Lei
authors: AL
authors: Feng
authors: Cheng-Jun
authors: CJ
authors: Zhou
authors: Xiao-Hong
authors: XH
authors: Liang
authors: Hai-Ting
authors: HT
authors: Mao
authors: Bi-Ping
authors: BP
authors: Deng
authors: Shi
authors: S
authors: Yan
authors: Jin-Tang
authors: JT
authors: Sun
authors: Lu-Tao
authors: LT
authors: Du
authors: Jia
authors: J
authors: Liu
authors: Qing-Jie
authors: QJ
authors: Wang
authors: Markus R
authors: MR
authors: Neckenig
authors: Qi-Feng
authors: QF
authors: Yang
authors: Xun
authors: X
authors: Qu
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D053804:Granzymes / Q000032:analysis; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D054398:Receptors, CCR4 / Q000032:analysis / Q000502:physiology*; D013274:Stomach Neoplasms / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C515354:CCR4 protein, human; D016328:NF-kappa B; D054398:Receptors, CCR4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D053804:Granzymes