Somasundaram Rajasekharan, Zhang Gao, Fukunaga-Kalabis Mizuho, Perego Michela, Krepler Clemens, Xu Xiaowei, Wagner Christine, Hristova Denitsa, Zhang Jie, Tian Tian, Wei Zhi, Liu Qin, Garg Kanika, Griss Johannes, Hards Rufus, Maurer Margarita, Hafner Christine, Mayerhöfer Marius, Karanikas Georgios, Jalili Ahmad, Bauer-Pohl Verena, Weihsengruber Felix, Rappersberger Klemens, Koller Josef, Lang Roland, Hudgens Courtney, Chen Guo, Tetzlaff Michael, Wu Lawrence, Frederick Dennie Tompers, Scolyer Richard A, Long Georgina V, Damle Manashree, Ellingsworth Courtney, Grinman Leon, Choi Harry, Gavin Brian J, Dunagin Margaret, Raj Arjun, Scholler Nathalie, Gross Laura, Beqiri Marilda, Bennett Keiryn, Watson Ian, Schaider Helmut, Davies Michael A, Wargo Jennifer, Czerniecki Brian J, Schuchter Lynn, Herlyn Dorothee, Flaherty Keith, Herlyn Meenhard, Wagner Stephan N
The Wistar Institute, Philadelphia, PA, 19104, USA.
Department of Pathology and Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Nat Commun. 2017 Sep 19;8(1):607. doi: 10.1038/s41467-017-00452-4.
In melanoma, therapies with inhibitors to oncogenic BRAF 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.
在黑色素瘤中，使用致癌性BRAF抑制剂的疗法非常有效，但由于耐药肿瘤亚群的出现，反应往往是短暂的。我们在此描述了一种通过肿瘤微环境获得性耐药的机制，该机制由人类肿瘤相关B细胞介导。人类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。由于异质性亚群的出现和FGFR-3的激活，B细胞衍生的IGF-1对于黑色素瘤对BRAF和MEK抑制剂的耐药性至关重要。一致地，黑色素瘤对BRAF和/或MEK抑制剂的耐药性与肿瘤中CD20和IGF-1转录水平的增加以及肿瘤相关B细胞中IGF-1的表达有关。此外，一项针对治疗耐药转移性黑色素瘤患者的试点试验的首批临床数据显示，通过抗CD20抗体清除B细胞具有抗肿瘤活性。我们的发现确立了一种通过肿瘤相关B细胞获得性治疗耐药的机制，具有重要的临床意义。黑色素瘤患者对BRAFV600E抑制剂的耐药性经常发生。在此，作者描述了一种由肿瘤相关B细胞衍生的IGF-1介导的获得性耐药的潜在机制。
