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      Th22 cells increase in poor prognosis multiple myeloma and promote tumor cell growth and survival

      1 , 2 , 3 , 1 , 2 , 1 , 2 , 3 , 2 , 4 , 2 , 5 , 6 , 7 , 7 , 8 , 3 , 9 , 10 , 1 , 2 , *

      Oncoimmunology

      Taylor & Francis

      bone marrow microenvironment, bone marrow mesenchymal stromal cells, CD4+ T helper lymphocytes, IL-22RA1, interleukin-13, interleukin-22, multiple myeloma, Th22 cells, Ab, antibody; BM, bone marrow; BMMCs, bone marrow mononuclear cells; DCs, dendritic cells; Dx, dexamethasone; ICS, intracellular cytokine staining; IFN, interferon; IL, interleukin; ISS, International Staging System; LCL, Epstein–Barr virus-transformed B lymphoblastoid cell line; Ln, lenalidomide; MGUS, monoclonal gammopathy of undetermined clinical significance; MM, multiple myeloma; MSC, mesenchymal stromal cell; PB, peripheral blood; PBMCs, peripheral blood mononuclear cells; pDCs, plasmacytoid dendritic cells; SMM, smoldering multiple myeloma; Th, T helper; TNF, tumor necrosis factor; Treg, regulatory T cells; WB, Western blot

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          Abstract

          There is increased production of plasmacytoid dendritic cells (pDCs) in the bone marrow (BM) of multiple myeloma (MM) patients and these favor Th22 cell differentiation. Here, we found that the frequency of interleukin (IL)-22 +IL-17 IL-13 + T cells is significantly increased in peripheral blood (PB) and BM of stage III and relapsed/refractory MM patients compared with healthy donors and patients with asymptomatic or stage I/II disease. Th22 cells cloned from the BM of MM patients were CCR6 +CXCR4 +CCR4 +CCR10 and produced IL-22 and IL-13 but not IL-17. Furthermore, polyfunctional Th22-Th2 and Th22-Th1 clones were identified based on the co-expression of additional chemokine receptors and cytokines (CRTh2 or CXCR3 and IL-5 or interferon gamma [IFNγ], respectively). A fraction of MM cell lines and primary tumors aberrantly expressed the IL-22RA1 and IL-22 induced STAT-3 phosphorylation, cell growth, and resistance to drug-induced cell death in MM cells. IL-13 treatment of normal BM mesenchymal stromal cells (MSCs) induced STAT-6 phosphorylation, adhesion molecule upregulation, and increased IL-6 production and significantly favored MM cell growth compared with untreated BM MSCs. Collectively, our data show that increased frequency of IL-22 +IL-17 IL-13 + T cells correlates with poor prognosis in MM through IL-22 and IL-13 protumor activity and suggest that interference with IL-22 and IL-13 signaling pathways could be exploited for therapeutic intervention.

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          Most cited references 38

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          Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells.

          Interleukin 22 (IL-22) is a cytokine produced by the T(H)-17 lineage of helper T cells and NK-22 subset of natural killer cells that acts on epithelial cells and keratinocytes and has been linked to skin homeostasis and inflammation. Here we characterize a population of human skin-homing memory CD4(+) T cells that expressed the chemokine receptors CCR10, CCR6 and CCR4 and produced IL-22 but neither IL-17 nor interferon-gamma (IFN-gamma). Clones isolated from this population produced IL-22 only and had low or undetectable expression of the T(H)-17 and T helper type 1 (T(H)1) transcription factors RORgammat and T-bet. The differentiation of T cells producing only IL-22 was efficiently induced in naive T cells by plasmacytoid dendritic cells in an IL-6- and tumor necrosis factor-dependent way. Our findings delineate a previously unknown subset of human CD4(+) effector T cells dedicated to skin pathophysiology.
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            The molecular classification of multiple myeloma.

            To better define the molecular basis of multiple myeloma (MM), we performed unsupervised hierarchic clustering of mRNA expression profiles in CD138-enriched plasma cells from 414 newly diagnosed patients who went on to receive high-dose therapy and tandem stem cell transplants. Seven disease subtypes were validated that were strongly influenced by known genetic lesions, such as c-MAF- and MAFB-, CCND1- and CCND3-, and MMSET-activating translocations and hyperdiploidy. Indicative of the deregulation of common pathways by gene orthologs, common gene signatures were observed in cases with c-MAF and MAFB activation and CCND1 and CCND3 activation, the latter consisting of 2 subgroups, one characterized by expression of the early B-cell markers CD20 and PAX5. A low incidence of focal bone disease distinguished one and increased expression of proliferation-associated genes of another novel subgroup. Comprising varying fractions of each of the other 6 subgroups, the proliferation subgroup dominated at relapse, suggesting that this signature is linked to disease progression. Proliferation and MMSET-spike groups were characterized by significant overexpression of genes mapping to chromosome 1q, and both exhibited a poor prognosis relative to the other groups. A subset of cases with a predominating myeloid gene expression signature, excluded from the profiling analyses, had more favorable baseline characteristics and superior prognosis to those lacking this signature.
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              Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets.

              Multiple myeloma is a plasma cell malignancy characterized by complex heterogeneous cytogenetic abnormalities. The bone marrow microenvironment promotes multiple myeloma cell growth and resistance to conventional therapies. Although multiple myeloma remains incurable, novel targeted agents, used alone or in combination, have shown great promise to overcome conventional drug resistance and improve patient outcome. Recent oncogenomic studies have further advanced our understanding of the molecular pathogenesis of multiple myeloma, providing the framework for new prognostic classification and identifying new therapeutic targets.
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                Author and article information

                Journal
                Oncoimmunology
                Oncoimmunology
                KONI
                Oncoimmunology
                Taylor & Francis
                2162-4011
                2162-402X
                3 February 2015
                May 2015
                : 4
                : 5
                Affiliations
                [1 ]Tumor Immunology Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy
                [2 ]Division of Immunology, Transplantation and Infectious Diseases; IRCCS San Raffaele Scientific Institute ; Milan, Italy
                [3 ]Hematology and Bone Marrow Transplantation Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy
                [4 ]Leukenia Immunotherapy Group; IRCCS San Raffaele Scientific Institute ; Milan, Italy
                [5 ]Experimental Hematology Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy
                [6 ]Pathology Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy
                [7 ]Division of Molecular Oncology; IRCCS San Raffaele Scientific Institute ; Milan, Italy
                [8 ]Functional Genomics of Cancer Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy
                [9 ]MolMed SpA ; Milan, Italy
                [10 ]Vita-Salute San Raffaele University ; Milan, Italy
                Author notes
                [* ]Correspondence to: Maria Pia Protti; Email: m.protti@ 123456hsr.it
                Article
                1005460
                10.1080/2162402X.2015.1005460
                4485827
                26155400
                © 2015 The Author(s). Published with license by Taylor & Francis Group, LLC© Giulia Di Lullo, Magda Marcatti, Silvia Heltai, Emanuela Brunetto, Cristina Tresoldi, Attilio Bondanza, Chiara Bonini, Maurilio Ponzoni, Giovanni Tonon, Fabio Ciceri, Claudio Bordignon, and Maria Pia Protti

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

                Page count
                Figures: 6, Tables: 2, References: 55, Pages: 13
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                Original Research

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