Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma.

Mice Animals Multiple Myeloma / therapy CD8-Positive T-Lymphocytes Immune Evasion T-Lymphocytes, Regulatory Immunotherapy / adverse effects Tumor Microenvironment / genetics

Journal

Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015

Informations de publication

Date de publication:
03 2023
Historique:
received: 02 02 2022
accepted: 09 12 2022
pubmed: 18 3 2023
medline: 25 3 2023
entrez: 17 3 2023
Statut: ppublish

Résumé

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

Identifiants

DOI: 10.1038/s41591-022-02178-3 PMID: 36928817 PMC: PMC10033443
pubmed: 36928817
doi: 10.1038/s41591-022-02178-3
pii: 10.1038/s41591-022-02178-3
pmc: PMC10033443
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

632-645

Subventions

Organisme : NCI NIH HHS
ID : P50 CA186781
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA242069
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197583
Pays : United States

Informations de copyright

© 2023. The Author(s).

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Auteurs

Marta 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.
ORCID: 0000-0001-6097-8244

Maria J 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.

Jon 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.
ORCID: 0000-0002-2017-4206

Amaia 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.
ORCID: 0000-0003-4408-0981

Maddalen 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.

Cristina 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.

Raquel 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.

Cesar Cobaleda (C)

Immune System Development and Function Unit, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas/Universidad Autonoma, Madrid, Spain.
ORCID: 0000-0003-3807-9204

Cirino 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.

Vicente 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.
ORCID: 0000-0003-1511-8354

Sergio 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.
ORCID: 0000-0003-1095-0715

Ibai 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.
ORCID: 0000-0002-5329-2225

Catarina 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.

Miren 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.

Marta Chesi (M)

Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA.
ORCID: 0000-0002-4024-8225

P Leif Bergsagel (PL)

Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA.
ORCID: 0000-0003-1523-7388

Maria J 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.

Maria J 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.
ORCID: 0000-0002-0374-3008

Elena Campos-Sanchez (E)

Immune System Development and Function Unit, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas/Universidad Autonoma, Madrid, Spain.

Jorge Martinez-Cano (J)

Immune System Development and Function Unit, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas/Universidad Autonoma, Madrid, Spain.
ORCID: 0000-0001-6809-5489

Carlos Panizo (C)

Department of Hematology, Clinica Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain.

Paula Rodriguez-Otero (P)

Department of Hematology, Clinica Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain.

Silvestre Vicent (S)

Program in Solid Tumors, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBERONC, Pamplona, Spain.
ORCID: 0000-0002-9457-6881

Giovanna Roncador (G)

Monoclonal Antibodies Unit, Biotechnology Program, Spanish National Cancer Research Centre CNIO, Madrid, Spain.

Patricia Gonzalez (P)

Monoclonal Antibodies Unit, Biotechnology Program, Spanish National Cancer Research Centre CNIO, Madrid, Spain.

Satoru Takahashi (S)

Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
ORCID: 0000-0002-8540-7760

Samuel G Katz (SG)

Department of Pathology, Yale School of Medicine, New Haven, CT, USA.

Loren D Walensky (LD)

Department of Pediatric Oncology and Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Shannon M Ruppert (SM)

Oncology Biomarker Development, Genentech, South San Francisco, CA, USA.

Elisabeth A Lasater (EA)

Department of Translational Oncology, Genentech, South San Francisco, CA, USA.

Maria Amann (M)

Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland.

Teresa Lozano (T)

Program of Immunology and Immunotherapy, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBEREHD, Pamplona, Spain.

Diana Llopiz (D)

Program of Immunology and Immunotherapy, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBEREHD, Pamplona, Spain.

Pablo Sarobe (P)

Program of Immunology and Immunotherapy, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBEREHD, Pamplona, Spain.

Juan J Lasarte (JJ)

Program of Immunology and Immunotherapy, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBEREHD, Pamplona, Spain.
ORCID: 0000-0003-1641-3881

Nuria Planell (N)

Translational Bioinformatics Unit, Navarra-Biomed, Public University of Navarra, IDISNA, Pamplona, Spain.

David 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.

Olga Kudryashova (O)

BostonGene, Waltham, MA, USA.
ORCID: 0000-0003-3320-7764

Anna Kurilovich (A)

BostonGene, Waltham, MA, USA.
ORCID: 0000-0002-3952-8609

Maria V Revuelta (MV)

Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA.
ORCID: 0000-0002-7922-0713

Leandro Cerchietti (L)

Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA.
ORCID: 0000-0003-0608-1350

Xabier 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.
ORCID: 0000-0002-6558-9560

Jesus 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.
ORCID: 0000-0002-9183-4857

Bruno 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.
ORCID: 0000-0003-1977-3815

Felipe 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.
ORCID: 0000-0001-6115-8790

Jose A 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.
ORCID: 0000-0002-7938-3950

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Preclinical models for prediction of...
questionsmedicales.fr › Eucaryotes › Animaux › Preclinical models for prediction of...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Paraprotéinémies › Myélome multiple › Preclinical models for prediction of...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › Lymphocytes T CD8+ › Preclinical models for prediction of...
questionsmedicales.fr › Phénomènes biologiques › Interactions hôte-microbes › Interactions hôte-pathogène › Échappement immunitaire › Preclinical models for prediction of...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › Sous-populations de lymphocytes T › Lymphocytes T régulateurs › Preclinical models for prediction of...
questionsmedicales.fr › Thérapeutique › Biothérapie › Immunothérapie › Preclinical models for prediction of...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › Preclinical models for prediction of...