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

Marta Larrayoz, Maria J Garcia-Barchino, Jon Celay, Amaia Etxebeste, Maddalen Jimenez, Cristina Perez, Raquel Ordoñez, Cesar Cobaleda, Cirino Botta, Vicente Fresquet, Sergio Roa, Ibai Goicoechea, Catarina Maia, Miren Lasaga, Marta Chesi, P Leif Bergsagel, Maria J Larrayoz, Maria J Calasanz, Elena Campos-Sanchez, Jorge Martinez-CanoCarlos Panizo, Paula Rodriguez-Otero, Silvestre Vicent, Giovanna Roncador, Patricia Gonzalez, Satoru Takahashi, Samuel G Katz, Loren D Walensky, Shannon M Ruppert, Elisabeth A Lasater, Maria Amann, Teresa Lozano, Diana Llopiz, Pablo Sarobe, Juan J Lasarte, Nuria Planell, David Gomez-Cabrero, Olga Kudryashova, Anna Kurilovich, Maria V Revuelta, Leandro Cerchietti, Xabier Agirre, Jesus San Miguel, Bruno Paiva, Felipe Prosper, Jose A Martinez-Climent

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 (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.
Original languageEnglish (US)
JournalNature Medicine
DOIs
StatePublished - Mar 16 2023

Bibliographical note

KAUST Repository Item: Exported on 2023-03-20
Acknowledgements: We are especially indebted to E. Ciordia, E. Elizalde and A. Espinal, veterinarians in our animal facilities, for excellent animal care. We also thank A. Raval for intellectual input and ideas, and excellent support; I. Melero for critical review of the manuscript; M.-Q. Du and S. Martinez-Pinilla for lymphoma pathology review; N. Varo for mouse laboratory analyses; C. Ortiz de Solorzano for bone imaging studies; Dreamgenics for bioinformatic support; N. Gutierrez, L.V. Valcarcel, S. Hervas and N. Casares for providing data and materials; M. Reth (University of Freiburg) for providing mb1-cre mice; and T. Regueiro, president of the Community of Spanish patients with MM, for support and dedication. This work was supported by the imCORE Network on behalf of F. Hoffmann-La Roche (NAV4 and NAV15 projects). Additional support was obtained from Spanish Ministry of Health - Instituto de Salud Carlos III (FIS), grants PI19/00818, PI20/00048, PI20/00260, CIBERONC no. CB16/12/00489 and no. CB16/12/00369, with support from FEDER (Fondo Europeo de Desarrollo Regional); Paula and Rodger Riney Foundation; Accelerator Award Program from the Spanish Association Against Cancer (AECC), Cancer Research United Kingdom (CRUK), and Associazione Italiana per la Ricerca sul Cancro (AIRC); Spanish Ministry of Education and Science, grants SAF2017-83061-R, PLEC2021-008094, and PID2021-128283OA; Fundacion Arnal Planelles; Fundacion Ramon Areces; Banco de Santander; European Research Council Starting Grant (MYELOMANEXT); CRIS Cancer Foundation (PR_EX_2020-02); AICR grant 24534, 2021; and Leukemia Lymphoma Society. M.C. and P.L.B. were supported by RO1 CA234181. L.C. was supported by R01 CA242069. M.L. was supported by a junior investigator grant from AECC. M.J.G.-B. was supported by Fundacion Arnal Planelles. J.C. was supported by AECC through the ‘Accelerator’ Award. S.R. was supported by RYC-2014-16399/MEC. J.M.C. is the recipient of an FPU fellowship from Universidad Autonoma de Madrid.

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Medicine

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