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Innate Immune Recognition Trigger CCL22 by Breast Tumor Cells” Author Manuscript Published OnlineFirst on August 18, 2011; DOI: 10.1158/0008-5472.CAN-11-0573 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Faget et al “innate immune recognition trigger CCL22 by breast tumor cells” Early detection of tumor cells by innate immune cells leads to Treg recruitment through CCL22 production by tumor cells Running title : innate immune recognition trigger CCL22 by breast tumor cells Julien Faget1,2,3, Cathy Biota1,2,3, Thomas Bachelot1,2,3, Michael Gobert1,2,3, Isabelle Treilleux1,2,3, Nadège Goutagny1,2,3, Isabelle Durand1,3, Sophie Léon-Goddard1,2,3, Jean Yves Blay1,2,3, Christophe Caux1,2,3 and Christine Ménétrier-Caux1,2,3 Affiliations : 1- Centre Léon Bérard, Lyon, France, 2- Université Lyon 1, F-69000 Lyon, France, 3- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France Corresponding author: Dr Christine MENETRIER-CAUX, Centre Léon Bérard, CRCL INSERM U1052/CNRS 5286, 28 rue Laennec, 69373 Lyon cedex 08, France; Tel : (33) 4 78 78 27 50; Fax : (33) 4 78 78 27 20; e-mail : [email protected] Key-words : CCL22, Treg, tumor cells, breast carcinoma, recruitment Scientific category: Immunology Conflict of interest disclosure: The authors declare no competing financial interest. Aknowledgments : JF and MG are grant holders of the Ligue Nationale contre le Cancer. This work was financially supported in part by grants from “le comité départemental du Rhône de Ligue Contre le Cancer “,the ARC association (ARC-5074), the Breast Cancer Research Fundation and Institut National du Cancer grant INCA ACI-63-04, ACI 2007-2009. Paper length Title: 120 characters, 19 words Abstract: 294 words Body Text (introduction/mat&meth/results/discussion/Figure legends): 4986 words Figures: 7 Supplementary Figures: 7 Supplementary Figure legends: 331 words References: 49 1/19 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 18, 2011; DOI: 10.1158/0008-5472.CAN-11-0573 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Faget et al “innate immune recognition trigger CCL22 by breast tumor cells” Abstract: In breast carcinomas, patient survival appears to be negatively impacted by the recruitment of regulatory T cells (Treg) within lymphoid aggregates by CCL22. However, the mechanisms underpining 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 (TNFα, IFNγ, IL-1β), contrasting with CCL17. Primary breast tumors and CD45+ infiltrating immune cells appeared to cooperate in driving CCL22 secretion, as demonstrated clearly in co-cultures of breast tumor cell lines and peripheral blood mononuclear cells (PBMC) or their supernatants. We determined that monocyte-derived IL-1β and TNFα are key players as monocyte depletion or neutralization of these cytokines attenuated secretion of CCL22. However, when purified monocytes were used, exogenous human IFNγ was also required to generate this response suggesting a role for IFNγ-producing cells within PBMC. In this setting, we found that human IFNγ could be replaced by the addition of (i) IL-2 or K562-activated NK cells or (ii) resting NK cells in the presence of anti-MHC class I antibody. Taken together, our results demonstrate a dialogue between NK and tumor cells leading to IFNγ secretion, which in turn associates with monocyte-derived IL-1β and TNFα to drive production of CCL22 by tumor cells and subsequent recruitment of Treg. As one validation of this conclusion in primary breast tumors, we demonstrated that NK 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, NK) imposes a selection for CCL22 secretion that recruit Treg to evade this early anti-tumor immune response. 2/19 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 18, 2011; DOI: 10.1158/0008-5472.CAN-11-0573 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Faget et al “innate immune recognition trigger CCL22 by breast tumor cells” Introduction Cancer immunosubversion is a process by which tumor cells escape destruction by the immune system through a variety of mechanisms including the production of immunosuppressive cytokines and the alteration of dendritic cells (DC) functions (1, 2). Several studies have shown that immune cells are present and functional in solid tumors and may promote both humoral and cellular anti-tumor immune responses. As an example, high levels of CD8+ T cells within the tumors have been associated with a better clinical prognosis in colorectal cancer (3). However, in most of the cases these T cells are unable to counteract tumor progression. In cancer patients, increased levels of CD4+CD25highFOXP3+ regulatory T cells (Treg), a lymphocyte subset with immuno-suppressive properties, are described in the peripheral blood, the primary tumor microenvironment and in the draining lymph nodes, supporting a role for Treg in cancer-induced immuno-suppression. However their effect on tumor progression varies according to the tumor type in humans. Treg have a negative impact on survival in lung, pancreatic, gastric, liver or ovarian carcinoma patients (4-7) whereas they may exert a beneficial role in B cell lymphoma, head and neck or colon carcinoma (8, 9) or have no impact in colon, prostate, renal or anal squamous cell carcinoma (10, 11) (for review (12)). We recently obtained evidences, in breast carcinoma, that selectively activated Treg accumulation within lymphoid aggregates, but not in the tumor bed, has a negative impact on patients’ survival (13). Elucidating the mechanisms involved in Treg trafficking and accumulation in the breast tumor environment is thereby critical for innovative therapeutic development to fight tumor induced immuno-suppression. Experiments in mice using Treg from CCR4-/- or conditional CCR4 knockout in FOXP3+ Treg compartment have recently identified the critical role of CCR4 in Treg trafficking in secondary lymphoid organs or tissues (14, 15). Curiel’s group strongly suggested a role for CCR4/CCL22 axis in Treg recruitment in ovarian ascitis (4). We recently demonstrated the selective loss of membrane CCR4 on tumor-associated Treg (TA-Treg) consecutive to an active recruitment through CCL22 and that breast tumors lacking CCL22 are not colonized by Treg independently of their CCL17 expression status (13) strongly suggesting the importance of CCL22 in TA-Treg recruitment within breast tumors. CCL22, a CC chemokine produced by myeloid DC (mDC), B cells, macrophages, keratinocytes or epithelial cells (6, 16, 17) and CCL17 closely related to CCL22, produced by monocyte derived DC (MoDC) (18) and keratinocytes (19), are two ligands for CCR4 (6, 20) preferentially expressed on Th2 lymphocytes(21) and Treg (for review (12)). In PBMC, 3/19 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 18, 2011; DOI: 10.1158/0008-5472.CAN-11-0573 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Faget et al “innate immune recognition trigger CCL22 by breast tumor cells” CCL22 is upregulated by IL-4 whereas it is downregulated by IFNγ treatment (22). In contrast, IFNγ favored CCL22 secretion by keratinocytes (16, 23) and intestinal epithelial cells (24). In the present study we demonstrated that breast tumor cells recognition by NK cells leads to their activation and IFNγ secretion that in turn triggers CCL22 production by tumor cells through cooperation with monocyte-derived IL-1β and TNFα. Material and methods Breast tumor cell lines culture: All tumor cell lines used in this study originated from ATCC except CLB-SAV generated in the laboratory. Cell lines were cultured in RPMI 1640 (invitrogen) completed with 10% foetal bovine serum (FBS) (Lonza, Vervier, Belgium), 100U/ml penicillin and 100µg/ml streptomycin (invitrogen)(complete medium) at 37°C in a 5% CO2 incubator. Primary breast tumors: Breast tumor tissues collected at the Centre Léon Bérard after patient informed consent were mechanically dilacerated to obtain “mechanic tumor disaggregation supernatants” and then subjected to enzymatic digestion as previously described(13). Flow cytometry analyses (ADP Cyan, Beckman Coulter) were performed to assess the percentage of NK cells (CD3-NKp46+) and macrophages (CD4+CD68+CD163+) (all from Becton Dickinson except for CD163 from eBiosciences and CD68 from Dako Cytomation) within primary tumor cell suspension after gating on CD45+ cells and data were analyzed with FlowJo analysis software (Tree Star). Immune cells (CD45+) or NK cells (CD3-CD56+) and macrophages (CD4lowCD163+) were purified on single cell suspension from breast primary tumor or ascitis respectively by cell sorting (FACS Aria, Becton Dickinson). Breast tumor supernatants (TumSN): Single-cell suspensions from primary or metastatic (ascitis, pleural effusion) breast
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