Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma.
Marta LarrayozMaria J Garcia-BarchinoJon CelayAmaia EtxebesteMaddalen JimenezCristina PerezRaquel OrdoñezCésar CobaledaCirino BottaVicente Jose FresquetSergio RoaIbai GoicoecheaCatarina MaiaMiren LasagaMarta ChesiPeter Leif BergsagelMaria J LarrayozMaría-José CalasanzElena Campos-SanchezJorge Martinez-CanoCarlos PanizoPaula Rodriguez-OteroSilvestre VincentGiovanna RoncadorPatricia GonzalezSatoru TakahashiSamuel G KatzLoren D WalenskyShannon M RuppertElisabeth A LasaterMaria AmannTeresa LozanoDiana LlopizPablo SarobeJuan Jose LasarteNuria PlanellDavid Gomez-CabreroOlga Mikhaylovna PlotnikovaAnna KurilovichMaria Victoria RevueltaLeandro CerchiettiXabier AgirreJesús San F MiguelJuan José LahuertaFelipe ProsperJose-Angel Martinez-ClimentPublished in: Nature medicine (2023)
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.
Keyphrases
- single cell
- induced apoptosis
- cell cycle arrest
- newly diagnosed
- transcription factor
- bone marrow
- multiple myeloma
- signaling pathway
- cell therapy
- genome wide
- pi k akt
- cell death
- oxidative stress
- end stage renal disease
- stem cells
- type diabetes
- immune response
- high throughput
- endoplasmic reticulum stress
- gene expression
- dna methylation
- cell proliferation
- copy number
- prognostic factors
- peripheral blood
- chronic kidney disease
- insulin resistance
- smoking cessation
- patient reported outcomes
- skeletal muscle
- toll like receptor
- cell cycle
- replacement therapy