Vemurafenib enhances MHC induction in BRAF(V600E) homozygous melanoma cells.
Vemurafenib enhances MHC induction in BRAF(V600E) homozygous melanoma cells.
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DOI：
10.4161/onci.22890
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发表时间：
2013-01-01
期刊：
影响因子：
7.2
通讯作者：
Pollack BP
中科院分区：
文献类型：
--
作者：
Sapkota B;Hill CE;Pollack BP
为了优化靶向激酶抑制剂和免疫疗法在黑色素瘤治疗中的整合，了解BRAFV600E突变状态和BRAFV600E抑制如何影响控制抗肿瘤免疫反应的基因表达将是至关重要的。由于主要组织相容性复合体（MHC）分子对于肿瘤细胞和淋巴细胞之间的相互作用至关重要，我们研究了brafv600e选择性抑制剂对MHC分子表达的影响。我们发现用vemurafenib治疗A375黑色素瘤细胞可增强干扰素γ和IFNα2b对MHC I类和II类分子的诱导作用。与这些发现一致，我们观察到强行过表达BRAFV600E具有相反的作用，可以抑制A375细胞中MHC I类分子的基线表达。利用其他8种黑色素瘤细胞系的进一步研究表明，vemurafenib介导的IFNγ对MHC诱导的增强仅发生在纯合子而非杂合子BRAFV600E突变的背景下。这些发现表明BRAFV600Eactivity直接影响MHC分子的表达和对I型和II型ifn的应答。此外，我们的数据表明，vemurafenib对免疫系统相关基因表达的影响可能取决于BRAFV600E突变的合子性，这在黑色素瘤患者中没有常规评估。
To optimally integrate targeted kinase inhibitors and immunotherapies in the treatment of melanoma, it will be critical to understand how BRAFV600E mutational status and BRAFV600E inhibition influence the expression of genes that govern antitumor immune responses. Because major histocompatibility complex (MHC) molecules are critical for interactions between tumor cells and lymphocytes, we investigated the impact of BRAFV600E-selective inhibitors on the expression of MHC molecules. We found that the treatment of A375 melanoma cells with vemurafenib enhances the induction of MHC Class I and Class II molecules by interferon γ and IFNα2b. Consistent with these findings, we observed that the forced overexpression of BRAFV600E has the opposite effect and can repress the baseline expression of MHC Class I molecules in A375 cells. Further studies utilizing eight other melanoma cell lines revealed that the vemurafenib-mediated enhancement of MHC induction by IFNγ only occurs in the context of homozygous, but not heterozygous, BRAFV600E mutation. These findings suggest that BRAFV600Eactivity directly influences the expression of MHC molecules and the response to Type I and Type II IFNs. Furthermore, our data suggest that the effect of vemurafenib on the expression of immune system-relevant genes may depend on the zygosity of the BRAFV600E mutation, which is not routinely assessed in melanoma patients.