Smith Michael P, Sanchez-Laorden Berta, O'Brien Kate, Brunton Holly, Ferguson Jennifer, Young Helen, Dhomen Nathalie, Flaherty Keith T, Frederick Dennie T, Cooper Zachary A, Wargo Jennifer A, Marais Richard, Wellbrock Claudia
Manchester Cancer Research Centre, Wellcome Trust Center for Cell Matrix Research, Faculty of Life Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, SW3 6JB, UK.
Cancer Discov. 2014 Oct;4(10):1214-1229. doi: 10.1158/2159-8290.CD-13-1007.
Recently, the rationale for combining targeted therapy with immunotherapy has come to light, but our understanding of the immune response during MAPK pathway inhibitor treatment is limited. We discovered that the immune microenvironment can act as a source of resistance to MAPK pathway-targeted therapy, and moreover during treatment this source becomes reinforced. In particular, we identified macrophage-derived TNFα as a crucial melanoma growth factor that provides resistance to MAPK pathway inhibitors through the lineage transcription factor MITF (microphthalmia transcription factor). Most strikingly, in BRAF-mutant melanomas of patients and BRAF(V600E) melanoma allografts, MAPK pathway inhibitors increased the number of tumor-associated macrophages, and TNFα and MITF expression. Inhibiting TNFα signaling with IκB kinase inhibitors profoundly enhanced the efficacy of MAPK pathway inhibitors by targeting not only the melanoma cells but also the microenvironment. In summary, we identify the immune microenvironment as a novel source of resistance and reveal a new strategy to improve the efficacy of targeted therapy in melanoma.
This study identifies the immune microenvironment as a source of resistance to MAPK pathway inhibitors through macrophage-derived TNFα, and reveals that in patients on treatment this source becomes reinforced. Inhibiting IκB kinase enhances the efficacy of MAPK pathway inhibitors, which identifies this approach as a potential novel strategy to improve targeted therapy in melanoma.
最近，联合靶向治疗与免疫治疗的基本原理已逐渐明晰，但我们对丝裂原活化蛋白激酶（MAPK）通路抑制剂治疗期间免疫反应的了解有限。我们发现免疫微环境可作为对MAPK通路靶向治疗产生耐药性的一个来源，而且在治疗期间这个来源会增强。具体而言，我们确定巨噬细胞衍生的肿瘤坏死因子α（TNFα）是一种关键的黑色素瘤生长因子，它通过谱系转录因子小眼畸形转录因子（MITF）对MAPK通路抑制剂产生耐药性。最显著的是，在患者的BRAF突变黑色素瘤和BRAF（V600E）黑色素瘤同种异体移植中，MAPK通路抑制剂增加了肿瘤相关巨噬细胞的数量以及TNFα和MITF的表达。用IκB激酶抑制剂抑制TNFα信号传导，不仅通过靶向黑色素瘤细胞，还通过靶向微环境，显著增强了MAPK通路抑制剂的疗效。总之，我们确定免疫微环境是一种新的耐药来源，并揭示了一种提高黑色素瘤靶向治疗疗效的新策略。
本研究确定免疫微环境是通过巨噬细胞衍生的TNFα对MAPK通路抑制剂产生耐药性的一个来源，并揭示在接受治疗的患者中这个来源会增强。抑制IκB激酶可增强MAPK通路抑制剂的疗效，这表明该方法是提高黑色素瘤靶向治疗的一种潜在新策略。
