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Mouse models of genetically heterogeneous multiple myeloma reveal mechanisms of immune evasion that predict clinical immunotherapy responses

ABSTRACT: Data from engineered fifteen mouse strains fully encompassing MM genetic heterogeneity that recapitulate the key pathogenic elements in human MM development and multiple myeloma patients.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE205447 | GEO | 2023/03/17

REPOSITORIES: GEO

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Pre-clinical models of genetically heterogeneous multiple myeloma reveal immune evasion mechanisms and predict clinical immunotherapy outcomes

Project description:The historical lack of pre-clinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers advancing therapeutic discoveries. To circumvent this limitation, we have generated fifteen genetically diverse models that developed bone marrow tumors fulfilling MM pathogenesis. Transcriptomic analysis of tumor plasma cells revealed that MYC activation regulates time to progression. Bone marrow cell composition analysis classified myeloma tumors into immune-cold and inflamed categories, which condition immune checkpoint blockade responses in mouse multiple myeloma models.

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

Project description: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.

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Project description: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.

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Pre-clinical models of genetically heterogeneous multiple myeloma reveal immune evasion mechanisms and predict clinical immunotherapy outcomes

Project description:Pre-clinical models of genetically heterogeneous multiple myeloma reveal immune evasion mechanisms and predict clinical immunotherapy outcomes

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Project description:Direct analysis of HLA-presented antigens by mass spectrometry provides a comprehensive view on the antigenic landscape of different tissues/malignancies and enables the identification of novel, pathophysiologically relevant T-cell epitopes. Here, we present a systematic and comparative study of the HLA class I and II presented, nonmutant antigenome of multiple myeloma (MM). Quantification of HLA surface expression revealed elevated HLA molecule counts on malignant plasma cells compared with normal B cells, excluding relevant HLA downregulation in MM. Analyzing the presentation of established myeloma-associated T-cell antigens on the HLA ligandome level, we found a substantial proportion of antigens to be only infrequently presented on primary myelomas or to display suboptimal degrees of myeloma specificity. However, unsupervised analysis of our extensive HLA ligand data set delineated a panel of 58 highly specific myeloma-associated antigens (including multiple myeloma SET domain containing protein) which are characterized by frequent and exclusive presentation on myeloma samples. Functional characterization of these target antigens revealed peptide-specific, preexisting CD8+ T-cell responses exclusively in myeloma patients, which is indicative of pathophysiological relevance. Furthermore, in vitro priming experiments revealed that peptide-specific T-cell responses can be induced in response-naive myeloma patients. Together, our results serve to guide antigen selection for T-cell–based immunotherapy of MM.

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