Aurora A kinase inhibition induces accumulation of SCLC tumor cells in mitosis with restored interferon signaling to increase response to PD-L1.
Aurora A kinase inhibition induces accumulation of SCLC tumor cells in mitosis with restored interferon signaling to increase response to PD-L1.
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Aurora A激酶抑制诱导SCLC肿瘤细胞在有丝分裂中积累，恢复干扰素信号传导以增加对PD-L1的应答。
DOI：
10.1016/j.xcrm.2023.101282
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发表时间：
2023-11-21
影响因子：
14.3
通讯作者：
Oser, Matthew G.
中科院分区：
文献类型：
--
作者：
Li, Yixiang;Mahadevan, Navin R.;Duplaquet, Leslie;Hong, Deli;Durmaz, Yavuz T.;Jones, Kristen L.;Cho, Hyeonseo;Morrow, Murry;Protti, Andrea;Poitras, Michael J.;Springer, Benjamin F.;Bronson, Roderick T.;Gong, Xueqian;Hui, Yu-Hua;Du, Jian;Southard, Jackson;Thai, Tran;Li, Shuqian;Lizotte, Patrick H.;Gokhale, Prafulla C.;Nguyen, Quang-De;Oser, Matthew G.
尽管小细胞肺癌（SCLC）具有高突变负荷，但程序性死亡配体1（PD-L1）免疫治疗仅适度增加生存期。SCLC的一个亚组失去了其ASCL 1神经内分泌表型并恢复了先天免疫信号传导（称为“炎性”亚型），对PD-L1具有持久的反应。一些SCLC对Aurora激酶抑制剂高度敏感，但早期试验显示反应短暂，这表明需要有效的治疗组合来增加其耐久性。使用具有免疫活性的SCLC基因工程小鼠模型（GEMM）和同基因异种移植物，我们显示了高度特异性Aurora A激酶抑制剂（LSN 3321213）和PD-L1组合的持久疗效。LSN 3321213导致肿瘤细胞在有丝分裂中蓄积，ASCL 1表达较低，干扰素靶基因和抗原呈递基因表达较高，以细胞周期依赖性方式模拟炎症亚型。这些数据表明，炎症基因的表达在SCLC的有丝分裂中恢复，这可以通过Aurora A激酶抑制来利用。Aurora A激酶抑制+ PD-L1免疫疗法在SCLC小鼠模型中具有持久疗效LSN 3321213和PD-L1增加肿瘤中的T淋巴细胞浸润LSN 3321213阻断具有高干扰素信号传导和MHC I类的有丝分裂肿瘤细胞Li et al.显示Aurora A激酶抑制导致SCLC肿瘤细胞在有丝分裂中积累，其中抗原呈递基因的高表达模拟免疫疗法应答性发炎肿瘤细胞状态。这促进了T淋巴细胞浸润，Aurora A激酶抑制+ PD-L1在免疫活性SCLC小鼠模型中具有持久的疗效。
Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the “inflammatory” subtype) have durable responses to PD-L1. Some SCLCs are highly sensitive to Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations are needed to increase their durability. Using immunocompetent SCLC genetically engineered mouse models (GEMMs) and syngeneic xenografts, we show durable efficacy with the combination of a highly specific Aurora A kinase inhibitor (LSN3321213) and PD-L1. LSN3321213 causes accumulation of tumor cells in mitosis with lower ASCL1 expression and higher expression of interferon target genes and antigen-presentation genes mimicking the inflammatory subtype in a cell-cycle-dependent manner. These data demonstrate that inflammatory gene expression is restored in mitosis in SCLC, which can be exploited by Aurora A kinase inhibition. Aurora A kinase inhibition + PD-L1 immunotherapy has durable efficacy in SCLC mouse models LSN3321213 and PD-L1 increases T-lymphocyte infiltration in tumors LSN3321213 blocks tumor cells in mitosis with high interferon signaling and MHC class I Li et al. show that Aurora A kinase inhibition causes accumulation of SCLC tumor cells in mitosis with high expression of antigen-presentation genes mimicking an immunotherapy-responsive inflamed tumor cell state. This promotes T-lymphocyte infiltration, and Aurora A kinase inhibition + PD-L1 has durable efficacy in immunocompetent SCLC mouse models.
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影响因子：
8.8
作者：
Borromeo MD;Savage TK;Kollipara RK;He M;Augustyn A;Osborne JK;Girard L;Minna JD;Gazdar AF;Cobb MH;Johnson JE
通讯作者：
Johnson JE
影响因子：
5.9
作者：
Cai L;Liu H;Huang F;Fujimoto J;Girard L;Chen J;Li Y;Zhang YA;Deb D;Stastny V;Pozo K;Kuo CS;Jia G;Yang C;Zou W;Alomar A;Huffman K;Papari-Zareei M;Yang L;Drapkin B;Akbay EA;Shames DS;Wistuba II;Wang T;Johnson JE;Xiao G;DeBerardinis RJ;Minna JD;Xie Y;Gazdar AF
通讯作者：
Gazdar AF
影响因子：
16.6
作者：
Dammed, Marcel A.;Bragelmann, Johannes;Sos, Martin L.
通讯作者：
Sos, Martin L.
影响因子：
48
作者：
Browaeys, Robin;Saelens, Wouter;Saeys, Yvan
通讯作者：
Saeys, Yvan
影响因子：
7.2
作者：
Alspach, Elise;Lussier, Danielle M.;Schreiber, Robert D.
通讯作者：
Schreiber, Robert D.