Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma.
Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma.
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DOI：
10.1038/s41591-022-02178-3
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发表时间：
2023-03
期刊：
影响因子：
82.9
通讯作者：
Martinez-Climent, Jose A.
中科院分区：
文献类型：
--
作者：
Larrayoz, Marta;Garcia-Barchino, Maria J.;Celay, Jon;Etxebeste, Amaia;Jimenez, Maddalen;Perez, Cristina;Ordonez, Raquel;Cobaleda, Cesar;Botta, Cirino;Fresquet, Vicente;Roa, Sergio;Goicoechea, Ibai;Maia, Catarina;Lasaga, Miren;Chesi, Marta;Bergsagel, P. Leif;Larrayoz, Maria J.;Calasanz, Maria J.;Campos-Sanchez, Elena;Martinez-Cano, Jorge;Panizo, Carlos;Rodriguez-Otero, Paula;Vicent, Silvestre;Roncador, Giovanna;Gonzalez, Patricia;Takahashi, Satoru;Katz, Samuel G.;Walensky, Loren D.;Ruppert, Shannon M.;Lasater, Elisabeth A.;Amann, Maria;Lozano, Teresa;Llopiz, Diana;Sarobe, Pablo;Lasarte, Juan J.;Planell, Nuria;Gomez-Cabrero, David;Kudryashova, Olga;Kurilovich, Anna;Revuelta, Maria V.;Cerchietti, Leandro;Agirre, Xabier;San Miguel, Jesus;Paiva, Bruno;Prosper, Felipe;Martinez-Climent, Jose A.
历史上缺乏反映多发性骨髓瘤（MM）遗传异质性的临床前模型，阻碍了治疗发现的进展。为了规避这一限制，我们筛选了在T细胞驱动免疫后携带在B淋巴细胞中组合活化的8种MM病变（NF-κB、KRAS、MYC、TP 53、BCL 2、细胞周期蛋白D1、MMSET/NSD 2和c-MAF）的小鼠。15个遗传多样性模型发展了符合MM发病机制的骨髓（BM）肿瘤。对500只小鼠和1,000名患者的综合分析揭示了一种常见的MAPK-MYC遗传途径，该途径加速了遗传异质性MM从前体状态进展的时间。MYC依赖性进展时间条件免疫逃避机制以不同方式重塑BM微环境。快速MYC驱动的进展者表现出大量活化/耗尽的CD 8 + T细胞，免疫抑制性调节性T（Treg）细胞减少，而缓慢进展者中的晚期MYC获得与较低的CD 8 + T细胞浸润和更丰富的Treg细胞相关。单细胞转录组学和功能测定将CD 8 + T细胞与Treg细胞的高比率定义为对免疫检查点阻断（ICB）的应答的预测因子。在临床系列研究中，高CD 8 + T/Treg细胞比率是未经治疗的郁积型MM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CD 8 + T细胞的细胞毒性或耗尽Treg细胞逆转了免疫疗法抗性并延长了MM控制。我们的实验模型使MM遗传和免疫学特征与临床前治疗反应相关，这可能为下一代免疫治疗试验提供信息。新的实验模型为了解遗传多样性多发性骨髓瘤的进展和对治疗的反应提供了急需的工具。
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. New experimental models provide much-needed tools for understanding how genetically diverse multiple myeloma progresses and evolves in response to therapy.
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影响因子：
46.9
作者：
Bolotin DA;Poslavsky S;Davydov AN;Frenkel FE;Fanchi L;Zolotareva OI;Hemmers S;Putintseva EV;Obraztsova AS;Shugay M;Ataullakhanov RI;Rudensky AY;Schumacher TN;Chudakov DM
通讯作者：
Chudakov DM
DOI：
10.1073/pnas.93.24.13931
发表时间：
1996-11-26
影响因子：
11.1
作者：
Bergsagel, PL;Chesi, M;Kuehl, WM
通讯作者：
Kuehl, WM
影响因子：
50.3
作者：
Calado DP;Zhang B;Srinivasan L;Sasaki Y;Seagal J;Unitt C;Rodig S;Kutok J;Tarakhovsky A;Schmidt-Supprian M;Rajewsky K
通讯作者：
Rajewsky K
DOI：
10.1126/science.aac9935
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Casey SC;Tong L;Li Y;Do R;Walz S;Fitzgerald KN;Gouw AM;Baylot V;Gütgemann I;Eilers M;Felsher DW
通讯作者：
Felsher DW
影响因子：
30.5
作者：
Dogan, Ismail;Bertocci, Barbara;Weill, Jean-Claude
通讯作者：
Weill, Jean-Claude