title: Th22 cells increase in poor prognosis multiple myeloma and promote tumor cell growth and survival.
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.
authors.affiliation: Tumor Immunology Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy ; Division of Immunology, Transplantation and Infectious Diseases; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Di Lullo
authors.affiliation: Hematology and Bone Marrow Transplantation Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Magda
authors.initials: M
authors.lastname: Marcatti
authors.affiliation: Tumor Immunology Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy ; Division of Immunology, Transplantation and Infectious Diseases; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Heltai
authors.affiliation: Tumor Immunology Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy ; Division of Immunology, Transplantation and Infectious Diseases; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Brunetto
authors.affiliation: Hematology and Bone Marrow Transplantation Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tresoldi
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases; IRCCS San Raffaele Scientific Institute ; Milan, Italy ; Leukenia Immunotherapy Group; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Attilio
authors.initials: A
authors.lastname: Bondanza
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases; IRCCS San Raffaele Scientific Institute ; Milan, Italy ; Experimental Hematology Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
authors.affiliation: Pathology Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy ; Division of Molecular Oncology; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Division of Molecular Oncology; IRCCS San Raffaele Scientific Institute ; Milan, Italy ; Functional Genomics of Cancer Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
authors.affiliation: Hematology and Bone Marrow Transplantation Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.affiliation: MolMed SpA ; Milan, Italy ; Vita-Salute San Raffaele University ; Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.affiliation: Tumor Immunology Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy ; Division of Immunology, Transplantation and Infectious Diseases; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Protti
keywords: 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; CD4+ T helper lymphocytes; IL-22RA1; Th22 cells; bone marrow mesenchymal stromal cells; bone marrow microenvironment; interleukin-13; interleukin-22; multiple myeloma