Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity.
Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity.
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极光激酶抑制使黑色素瘤细胞对T细胞介导的细胞毒敏感。
DOI：
10.1007/s00262-020-02748-9
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Hwu P
中科院分区：
文献类型：
--
作者：
Punt S;Malu S;McKenzie JA;Manrique SZ;Doorduijn EM;Mbofung RM;Williams L;Silverman DA;Ashkin EL;Dominguez AL;Wang Z;Chen JQ;Maiti SN;Tieu TN;Liu C;Xu C;Forget MA;Haymaker C;Khalili JS;Satani N;Muller F;Cooper LJN;Overwijk WW;Amaria RN;Bernatchez C;Heffernan TP;Peng W;Roszik J;Hwu P
尽管免疫疗法已经取得了令人印象深刻的持久临床反应，但许多癌症对免疫疗法仅暂时或根本没有反应。为了发现新的、可靶向的免疫治疗抗性机制，在与自体肿瘤浸润淋巴细胞（TIL）共培养之前，用576个开放阅读框转导患者来源的黑素瘤细胞系，或将其暴露于850种生物活性化合物的阵列文库。探讨了靶点与TIL诱导凋亡的协同作用以及抑制TIL抗性的机制。对来自接受转移性黑色素瘤免疫治疗的患者的肿瘤样品进行基因表达分析。最后，在多个临床前模型中研究了抑制最高靶标对免疫治疗功效的影响。在两个互补筛选中，Aurora激酶被鉴定为黑色素瘤细胞对T细胞介导的细胞毒性的抗性的介体。Aurora激酶抑制剂在体外被验证与T细胞介导的细胞毒性协同作用。Aurora激酶抑制介导的对T细胞毒性的敏感性被证明部分由p21介导的细胞衰老诱导驱动。Aurora激酶及相关蛋白的表达水平与黑色素瘤患者的免疫浸润、免疫治疗反应和生存率呈负相关。Aurora激酶抑制在体内与免疫疗法组合时显示出可变的反应，表明其活性被肿瘤微环境中的其他因素改变。这些数据表明，Aurora激酶抑制增强T细胞的体外细胞毒性，并可以增强体内抗肿瘤免疫力，在一些但不是所有的设置。需要进一步的研究来确定这种治疗干预的原发性耐药机制。本文的在线版本（10.1007/s 00262 -020-02748-9）包含补充材料，可供授权用户使用。
Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, or exposed to arrayed libraries of 850 bioactive compounds, prior to co-culture with autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs to induce apoptosis, and the mechanisms of inhibiting resistance to TILs were interrogated. Gene expression analyses were performed on tumor samples from patients undergoing immunotherapy for metastatic melanoma. Finally, the effect of inhibiting the top targets on the efficacy of immunotherapy was investigated in multiple preclinical models. Aurora kinase was identified as a mediator of melanoma cell resistance to T-cell-mediated cytotoxicity in both complementary screens. Aurora kinase inhibitors were validated to synergize with T-cell-mediated cytotoxicity in vitro. The Aurora kinase inhibition-mediated sensitivity to T-cell cytotoxicity was shown to be partially driven by p21-mediated induction of cellular senescence. The expression levels of Aurora kinase and related proteins were inversely correlated with immune infiltration, response to immunotherapy and survival in melanoma patients. Aurora kinase inhibition showed variable responses in combination with immunotherapy in vivo, suggesting its activity is modified by other factors in the tumor microenvironment. These data suggest that Aurora kinase inhibition enhances T-cell cytotoxicity in vitro and can potentiate antitumor immunity in vivo in some but not all settings. Further studies are required to determine the mechanism of primary resistance to this therapeutic intervention. The online version of this article (10.1007/s00262-020-02748-9) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Chacon JA;Wu RC;Sukhumalchandra P;Molldrem JJ;Sarnaik A;Pilon-Thomas S;Weber J;Hwu P;Radvanyi L
通讯作者：
Radvanyi L
影响因子：
10.1
作者：
Cooper ZA;Juneja VR;Sage PT;Frederick DT;Piris A;Mitra D;Lo JA;Hodi FS;Freeman GJ;Bosenberg MW;McMahon M;Flaherty KT;Fisher DE;Sharpe AH;Wargo JA
通讯作者：
Wargo JA
影响因子：
7.5
作者：
Carmena M;Ruchaud S;Earnshaw WC
通讯作者：
Earnshaw WC
影响因子：
6.5
作者：
Anton Puig-Butille, Joan;Vinyals, Antonia;Fabra, Angels
通讯作者：
Fabra, Angels
影响因子：
64.8
作者：
Kang, Tae-Won;Yevsa, Tetyana;Zender, Lars
通讯作者：
Zender, Lars