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Pre-clinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma

ABSTRACT: Multiple myeloma (MM) is a neoplasia of bone marrow (BM) plasma cells that remains largely incurable with current treatment. Advancing therapeutic discoveries has been hampered by the lack of genetically heterogeneous models of MM. To circumvent this limitation, we engineered fifteen mouse models carrying combinations of eight MM genetic drivers, which fulfilled the pathogenesis of human disease including progression from premalignant states under immune surveillance. Integrative analyses of ⁓500 mice and ⁓1,000 patients revealed a MAPK-MYC genetic pathway that regulates time to progression and immune escape mechanisms across genetically heterogeneous tumors. During progression, MYC-dependent and independent remodeling of the BM microenvironment divided MM into immune categories with predominance of selected T-cell subpopulations, which dictated immunotherapy responses. Experimental targeting of the cytotoxic or immunosuppressive T-cell states observed in refractory MM patients enhanced immunotherapy effectiveness. Our resource enabled characterization of MM cell-intrinsic and immunological traits at unprecedented levels, which will accelerate the translation of personalized immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE220997 | GEO | 2023/01/31

REPOSITORIES: GEO

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