Roncador, G. (Giovanna)

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    Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma
    (2023) Perez, C. (Cristina); Fresquet, V. (Vicente); Maia, C. (Catarina); Gomez-Cabrero, D. (David); Lasaga, M. (Miren); Celay, J. (Jon); Lozano-Moreda, T. (Teresa); Vicent, S. (Silvestre); Roncador, G. (Giovanna); Goicoechea, I. (Ibai); García-Barchino, M.J. (María José); Martinez-Climent, J.A. (José Ángel); Walensky, L.D. (Loren D.); Panizo, C. (Carlos); Lasater, E.A. (Elisabeth A.); Katz, S.G. (Samuel G.); Larrayoz, M. (Marta); Roa, S. (Sergio); Bergsagel, P.L. (P. Leif); Gonzalez, P. (Patricia); Botta, C. (Cirino); Ordóñez-Ciriza, R. (Raquel); Takahashi, S. (Satoru); Aguirre-Ena, X. (Xabier); Kurilovich, A. (Anna); Amann, M. (Maria); Rodriguez-Otero, P. (Paula); Llopiz, D. (Diana); Paiva, B. (Bruno); Sarobe, P. (Pablo); Campos-Sanchez, E. (Elena); Ruppert, S.M. (Shannon M.); Martínez-Cano, J. (Jorge); Larrayoz, M.J. (María J.); Revuelta, M.V. (Maria V.); Cobaleda, C. (César); Prosper-Cardoso, F. (Felipe); Etxebeste-Mitxeltorena, A. (Amaia); Calasanz-Abinzano, M.J. (Maria Jose); San-Miguel, J.F. (Jesús F.); Cerchietti, L. (Leandro); Planell, N. (Núria); Jiménez-Andrés, M. (Maddalen); Kudryashova, O. (Olga); Chesi, M. (Marta); Lasarte, J.J. (Juan José)
    The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-kappaB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of 500 mice and 1,000 patients revealed a common MAPK-MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8+ T cells with reduced immunosuppressive regulatory T (Treg) cells, while late MYC acquisition in slow progressors was associated with lower CD8+ T cell infiltration and more abundant Treg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8+ T cells versus Treg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8+ T/Treg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8+ T cell cytotoxicity or depleting Treg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials.
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    Generation of a new monoclonal antibody against MALT1 by genetic immunization
    (Mary Ann Liebert, Inc., 2007) Cigudosa, J.C. (Juan Cruz); Roncador, G. (Giovanna); Martinez-Climent, J.A. (José Ángel); Maestre, L. (Lorena); Fontan, L. (Lorena); Garcia, J.F. (José Francisco)
    Genetic immunization (GI), which is primarily used for vaccine purposes, is a method for producing antibodies to a protein by delivering the gene encoding the protein as a eukaryotic expression vector instead of the protein itself. The mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) is one of the most likely candidates for involvement in pathogenesis of MALT lymphoma and probably of multiple myelomas. In the present work we describe the production and characterization of a mouse monoclonal antibody (mAb) directed against MALT1 and the study of MALT1 protein expression in a large series of lymphomas and myeloma cell lines. The full-length coding sequence of human MALT1 was inserted into pcDNA3 vector and delivered into mouse skin using a helium gene gun. Six new mAbs against the MALT1 molecule were produced. In order to characterize and confirm the specificity of these mAbs, Western blot (WB) and immunoprecipitation (IP) analyses were performed. A new anti-MALT1 mAb was selected and tested in a large series of cell lines. These results confirm that GI is a reliable and effective alternative method for production of mAbs, allowing accurate and sensitive detection and screening of proteins by WB.