title: Early detection of tumor cells by innate immune cells leads to T(reg) recruitment through CCL22 production by tumor cells.
abstract: In breast carcinomas, patient survival seems to be negatively affected by the recruitment of regulatory T cells (T(reg)) within lymphoid aggregates by CCL22. However, the mechanisms underpinning this process, which may be of broader significance in solid tumors, have yet to be described. In this study, we determined how CCL22 production is controlled in tumor cells. In human breast carcinoma cell lines, CCL22 was secreted at low basal levels that were strongly increased in response to inflammatory signals [TNF-α, IFN-γ, and interleukin (IL)-1β], contrasting with CCL17. Primary breast tumors and CD45(+) infiltrating immune cells appeared to cooperate in driving CCL22 secretion, as shown clearly in cocultures of breast tumor cell lines and peripheral blood mononuclear cells (PBMC) or their supernatants. We determined that monocyte-derived IL-1β and TNF-α are key players as monocyte depletion or neutralization of these cytokines attenuated secretion of CCL22. However, when purified monocytes were used, exogenous human IFN-γ was also required to generate this response suggesting a role for IFN-γ-producing cells within PBMCs. In this setting, we found that human IFN-γ could be replaced by the addition of (i) IL-2 or K562-activated natural killer (NK) cells or (ii) resting NK cells in the presence of anti-MHC class I antibody. Taken together, our results show a dialogue between NK and tumor cells leading to IFN-γ secretion, which in turn associates with monocyte-derived IL-1β and TNF-α to drive production of CCL22 by tumor cells and subsequent recruitment of T(reg). As one validation of this conclusion in primary breast tumors, we showed that NK cells and macrophages tend to colocalize within tumors. In summary, our findings suggest that at early times during tumorigenesis, the detection of tumor cells by innate effectors (monocytes and NK cells) imposes a selection for CCL22 secretion that recruits T(reg) to evade this early antitumor immune response.
authors.affiliation: Centre Léon Bérard, F-69000 Lyon, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Faget
authors.forename: Cathy
authors.initials: C
authors.lastname: Biota
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.forename: Michael
authors.initials: M
authors.lastname: Gobert
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.forename: Nadège
authors.initials: N
authors.lastname: Goutagny
authors.forename: Isabelle
authors.initials: I
authors.lastname: Durand
authors.forename: Sophie
authors.initials: S
authors.lastname: Léon-Goddard
authors.forename: Jean Yves
authors.initials: JY
authors.lastname: Blay
authors.forename: Christophe
authors.initials: C
authors.lastname: Caux
authors.forename: Christine
authors.initials: C
authors.lastname: Ménétrier-Caux
mesh_terms: D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication; D045744:Cell Line, Tumor; D054422:Chemokine CCL22 / Q000096:biosynthesis*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C515482:CCL22 protein, human; D054422:Chemokine CCL22; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma