Résumé
We recently obtained evidences, in breast carcinoma, that regulatory T cells (Treg) localized within lymphoid aggregates, but not in the tumor bed, have a negative impact on patients’ survival. Immunohistochemical analysis on paraffin embedded sections of tumors demonstrated correlation between CCL22 production tumor cells and Treg infiltration thus identifying CCL22 as a key mediator of intratumoral Treg recruitment (Gobert M., Cancer Res vol 69, p2000-9, 2009). Herein we decipher the mechanisms regulating CCL22 production by tumor cells. In vitro, human breast epithelial tumor cell lines secreted low CCL22 levels that were strongly increased in response to inflammatory signals (TNFα, IFNγ and IL-1β or their combination). Using an in vitro model we demonstrated that breast tumor cell lines (MCF-7, MDA-MB453, CLB-SAV, BT-474) but not immortalized normal breast epithelial cell line (Telma) secreted functional CCL22 in response to culture with PBMC or their supernatants. Addition of IL-1RA and anti-TNFα abrogated the CCL22 secretion demonstrating the importance of Il-1β and TNFα in CCL22 production. Depletion experiments demonstrated a major role of monocytes within PBMC in i) the induction of CCL22 and ii) the production of IL-1β and TNFα. However, co-culture of tumor cells with purified monocytes was not sufficient to reproduce the PBMC effects. The addition of rhIFNγ to tumor cell and monocyte co-cultures restored the CCL22 production by tumor cells and that of IL-1β by monocytes suggesting a role of IFNγ producing cells (T cells or NK cells) within PBMC. Taken together, these results demonstrate a dialogue between monocytes, tumor cells and IFNγ producers (NK or T cells) leading, through monocyte-derived IL-1β and TNFα, to CCL22 production by tumor cells and Treg recruitment. These observations would suggest that early tumor cell detection by innate effectors (monocytes, NK) would trigger CCL22 production by tumor cells and not normal mammary epithelial cells leading to Treg recruitment as a mechanism to stop the anti-tumor immune reactivity. Citation Format: Authors. Abstract title [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1341.