多发性骨髓瘤（MM）的遗传异质性在预临床模型中的历史性缺失阻碍了治疗研究的进展。为了克服这一限制，我们筛选出一种具有携带八个MM病变（NF-κB，KRAS，MYC，TP53，BCL2，cyclin D1，MMSET / NSD2和c-MAF）的转基因小鼠，这八个病变在B淋巴细胞中组合激活，随后通过T细胞驱动的免疫接种。十五个遗传多样化的模型发展出符合MM病理发生的骨髓（BM）肿瘤。对约500只小鼠和约1,000名患者进行的综合分析揭示了一条共同的MAPK-MYC遗传途径，它加速了从先兆状态到遗传异质性MM的进展时间。MYC依赖的进展时间条件免疫逃避机制，以不同方式重塑了BM微环境。快速的MYC驱动进展者表现出大量激活/疲惫的CD8+ T细胞，以及减少的免疫抑制性调节T（Treg）细胞，而在慢速进展者中获得的MYC则与较低的CD8+ T细胞浸润和更丰富的Treg细胞相关联。单细胞转录组学和功能分析定义了CD8+ T细胞与Treg细胞的高比例作为免疫检查点阻断（ICB）反应的预测因子。在临床试验中，未经治疗的微小型MM中高CD8+ T / Treg细胞比例是早期进展的基础，并与接受Len / Dex治疗的新诊断MM患者的早期复发相关。在ICB难治性MM模型中，增加CD8+ T细胞细胞毒活性或消耗Treg细胞可以逆转免疫疗法耐受性并产生长时间的MM控制。我们的实验模型使得MM遗传和免疫特征与临床治疗反应相互关联，这可能有助于下一代免疫疗法试验。 ©2023年。作者。

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.© 2023. The Author(s).