Tumor-associated B-cells induce tumor heterogeneity and therapy resistance.
Tumor-associated B-cells induce tumor heterogeneity and therapy resistance.
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DOI：
10.1038/s41467-017-00452-4
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发表时间：
2017-09-19
影响因子：
16.6
通讯作者：
Wagner SN
中科院分区：
文献类型：
--
作者：
Somasundaram R;Zhang G;Fukunaga-Kalabis M;Perego M;Krepler C;Xu X;Wagner C;Hristova D;Zhang J;Tian T;Wei Z;Liu Q;Garg K;Griss J;Hards R;Maurer M;Hafner C;Mayerhöfer M;Karanikas G;Jalili A;Bauer-Pohl V;Weihsengruber F;Rappersberger K;Koller J;Lang R;Hudgens C;Chen G;Tetzlaff M;Wu L;Frederick DT;Scolyer RA;Long GV;Damle M;Ellingsworth C;Grinman L;Choi H;Gavin BJ;Dunagin M;Raj A;Scholler N;Gross L;Beqiri M;Bennett K;Watson I;Schaider H;Davies MA;Wargo J;Czerniecki BJ;Schuchter L;Herlyn D;Flaherty K;Herlyn M;Wagner SN
在黑色素瘤中，使用致癌BRAFV 600 E抑制剂的治疗非常有效，但由于耐药肿瘤亚群的出现，应答通常是短暂的。我们在这里描述了通过肿瘤微环境获得性耐药的机制，这是由人类肿瘤相关B细胞介导的。人黑色素瘤细胞组成性地产生生长因子FGF-2，其激活肿瘤浸润性B细胞以产生生长因子IGF-1。由于异质亚群的出现和FGFR-3的活化，B细胞衍生的IGF-1对于黑色素瘤对BRAF和MEK抑制剂的抗性至关重要。一致地，黑素瘤对BRAF和/或MEK抑制剂的抗性与肿瘤中增加的CD 20和IGF-1转录物水平以及肿瘤相关B细胞中IGF-1表达相关。此外，来自治疗抗性转移性黑色素瘤患者的初步试验的第一个临床数据显示通过抗CD 20抗体的B细胞消耗的抗肿瘤活性。我们的研究结果建立了通过肿瘤相关B细胞获得性治疗耐药的机制，具有重要的临床意义。对BRAFV 600 E抑制剂的耐药性通常发生在黑色素瘤患者中。在这里，作者描述了一个潜在的机制，获得性耐药介导的肿瘤相关的B细胞衍生的IGF-1。
In melanoma, therapies with inhibitors to oncogenic BRAFV600E are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3. Consistently, resistance of melanomas to BRAF and/or MEK inhibitors is associated with increased CD20 and IGF-1 transcript levels in tumors and IGF-1 expression in tumor-associated B cells. Furthermore, first clinical data from a pilot trial in therapy-resistant metastatic melanoma patients show anti-tumor activity through B-cell depletion by anti-CD20 antibody. Our findings establish a mechanism of acquired therapy resistance through tumor-associated B cells with important clinical implications. Resistance to BRAFV600E inhibitors often occurs in melanoma patients. Here, the authors describe a potential mechanism of acquired drug resistance mediated by tumor-associated B cells-derived IGF-1.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
影响因子：
15.9
作者：
Guinea-Viniegra, Juan;Zenz, Rainer;Wagner, Erwin F.
通讯作者：
Wagner, Erwin F.
影响因子：
45.3
作者：
Balch, Charles M.;Gershenwald, Jeffrey E.;Sondak, Vernon K.
通讯作者：
Sondak, Vernon K.