Scientific publications

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

Mar 16, 2023 | Magazine: Nature Medicine

Marta Larrayoz  1 , Maria J Garcia-Barchino  1 , Jon Celay  1 , Amaia Etxebeste  1 , Maddalen Jimenez  1 , Cristina Perez  1 , Raquel Ordoñez  1 , Cesar Cobaleda  2 , Cirino Botta  1   3 , Vicente Fresquet  1 , Sergio Roa  1 , Ibai Goicoechea  1 , Catarina Maia  1 , Miren Lasaga  1 , Marta Chesi  4 , P Leif Bergsagel  4 , Maria J Larrayoz  1 , Maria J Calasanz  1 , Elena Campos-Sanchez  2 , Jorge Martinez-Cano  2 , Carlos Panizo  5 , Paula Rodriguez-Otero  5 , Silvestre Vicent  6 , Giovanna Roncador  7 , Patricia Gonzalez  7 , Satoru Takahashi  8 , Samuel G Katz  9 , Loren D Walensky  10 , Shannon M Ruppert  11 , Elisabeth A Lasater  12 , Maria Amann  13 , Teresa Lozano  14 , Diana Llopiz  14 , Pablo Sarobe  14 , Juan J Lasarte  14 , Nuria Planell  15 , David Gomez-Cabrero  15   16 , Olga Kudryashova  17 , Anna Kurilovich  17 , Maria V Revuelta  18 , Leandro Cerchietti  18 , Xabier Agirre  1 , Jesus San Miguel  1   5 , Bruno Paiva  1   5 , Felipe Prosper  1   5 , Jose A Martinez-Climent  19


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.

CITATION  Nat Med. 2023 Mar 16.  doi: 10.1038/s41591-022-02178-3

Our authors

Dr. Marta Larráyoz Ilundáin
María José García Barchino
Dr. Jon Celay Leoz
Dr. Maddalen Jiménez Andrés
Vicente José Fresquet Arnau
Dr. Marta Larráyoz Ilundáin
Dr. Teresa Lozano Moreda
Dr. Diana Llópiz Khatchikian