학술논문
Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma.
Document Type
Academic Journal
Author
Larrayoz M; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Garcia-Barchino MJ; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Celay J; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Etxebeste A; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Jimenez M; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Perez C; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Ordoñez R; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Cobaleda C; Immune System Development and Function Unit, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas/Universidad Autonoma, Madrid, Spain.; Botta C; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.; Fresquet V; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Roa S; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Goicoechea I; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Maia C; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Lasaga M; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Chesi M; Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA.; Bergsagel PL; Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA.; Larrayoz MJ; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Calasanz MJ; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Campos-Sanchez E; Immune System Development and Function Unit, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas/Universidad Autonoma, Madrid, Spain.; Martinez-Cano J; Immune System Development and Function Unit, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas/Universidad Autonoma, Madrid, Spain.; Panizo C; Department of Hematology, Clinica Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain.; Rodriguez-Otero P; Department of Hematology, Clinica Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain.; Vicent S; Program in Solid Tumors, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBERONC, Pamplona, Spain.; Roncador G; Monoclonal Antibodies Unit, Biotechnology Program, Spanish National Cancer Research Centre CNIO, Madrid, Spain.; Gonzalez P; Monoclonal Antibodies Unit, Biotechnology Program, Spanish National Cancer Research Centre CNIO, Madrid, Spain.; Takahashi S; Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.; Katz SG; Department of Pathology, Yale School of Medicine, New Haven, CT, USA.; Walensky LD; Department of Pediatric Oncology and Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.; Ruppert SM; Oncology Biomarker Development, Genentech, South San Francisco, CA, USA.; Lasater EA; Department of Translational Oncology, Genentech, South San Francisco, CA, USA.; Amann M; Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland.; Lozano T; Program of Immunology and Immunotherapy, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBEREHD, Pamplona, Spain.; Llopiz D; Program of Immunology and Immunotherapy, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBEREHD, Pamplona, Spain.; Sarobe P; Program of Immunology and Immunotherapy, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBEREHD, Pamplona, Spain.; Lasarte JJ; Program of Immunology and Immunotherapy, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBEREHD, Pamplona, Spain.; Planell N; Translational Bioinformatics Unit, Navarra-Biomed, Public University of Navarra, IDISNA, Pamplona, Spain.; Gomez-Cabrero D; Translational Bioinformatics Unit, Navarra-Biomed, Public University of Navarra, IDISNA, Pamplona, Spain.; Biological and Environmental Sciences & Engineering Division, King Abdullah University of Science & Technology, Thuwal, Kingdom of Saudi Arabia.; Kudryashova O; BostonGene, Waltham, MA, USA.; Kurilovich A; BostonGene, Waltham, MA, USA.; Revuelta MV; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA.; Cerchietti L; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA.; Agirre X; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; San Miguel J; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Department of Hematology, Clinica Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain.; Paiva B; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Department of Hematology, Clinica Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain.; Prosper F; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.; Department of Hematology, Clinica Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain.; Martinez-Climent JA; Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain. jamcliment@unav.es.
Source
Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE
Subject
Language
English
Abstract
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-κB, 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 (T reg ) cells, while late MYC acquisition in slow progressors was associated with lower CD8 + T cell infiltration and more abundant T reg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8 + T cells versus T reg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8 + T/T reg 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 T reg 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.
(© 2023. The Author(s).)
(© 2023. The Author(s).)