Selective BRAFV600E Inhibition Enhances T-Cell Recognition of Melanoma without Affecting Lymphocyte Function
Selective BRAFV600E Inhibition Enhances T-Cell Recognition of Melanoma without Affecting Lymphocyte Function
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DOI：
10.1158/0008-5472.can-10-0118
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发表时间：
2010-07-01
期刊：
影响因子：
11.2
通讯作者：
Wargo, Jennifer A.
中科院分区：
文献类型：
--
作者：
Boni, Andrea;Cogdill, Alexandria P.;Wargo, Jennifer A.
针对BRAF/丝裂原活化蛋白激酶（MAPK）通路的靶向治疗是治疗黑色素瘤的一种有前途的新治疗方法。用选择性BRAF抑制剂治疗导致高初始响应率，但响应持续时间有限。为了解决这个问题，研究人员建议将这种疗法与其他靶向药物结合，通过不同的致癌途径解决冗余和信号传导的问题。另一种方法是将BRAF/MAPK靶向药物与免疫疗法相结合。初步证据表明，致癌BRAF（BRAF（V600 E））有助于免疫逃逸，通过MAPK途径抑制阻断其活性导致黑素细胞分化抗原（MDA）的表达增加。MDA的识别是对黑素瘤的免疫应答的关键组成部分，并且几种形式的免疫疗法利用这种识别。在抑制BRAF/MAPK的各种方法中，广泛的MAPK途径抑制可能对T淋巴细胞功能具有有害影响。在这里，我们证实了致癌BRAF的作用，免疫逃避黑色素瘤细胞通过抑制MDA。我们表明，在黑色素瘤细胞系和肿瘤细胞中，MAPK/细胞外信号调节激酶激酶（MEK）抑制剂或BRAF（V600 E）的特异性抑制剂抑制MAPK通路导致MDA水平增加，这与抗原特异性T淋巴细胞的识别能力提高有关。然而，用MEK抑制剂治疗损害T淋巴细胞功能，而用BRAF的特异性抑制剂（V600 E）治疗后T细胞功能得以保留。这些发现表明，由致癌BRAF介导的黑色素瘤的免疫逃避可以通过靶向BRAF抑制而逆转，而不损害T细胞功能。这些研究结果对联合激酶靶向治疗加免疫治疗黑色素瘤具有重要意义。Cancer Res; 70（13）; 5213-9. (C)2010年AACR。
Targeted therapy against the BRAF/mitogen-activated protein kinase (MAPK) pathway is a promising new therapeutic approach for the treatment of melanoma. Treatment with selective BRAF inhibitors results in a high initial response rate but limited duration of response. To counter this, investigators propose combining this therapy with other targeted agents, addressing the issue of redundancy and signaling through different oncogenic pathways. An alternative approach is combining BRAF/MAPK-targeted agents with immunotherapy. Preliminary evidence suggests that oncogenic BRAF (BRAF(V600E)) contributes to immune escape and that blocking its activity via MAPK pathway inhibition leads to increased expression of melanocyte differentiation antigens (MDA). Recognition of MDAs is a critical component of the immunologic response to melanoma, and several forms of immunotherapy capitalize on this recognition. Among the various approaches to inhibiting BRAF/MAPK, broad MAPK pathway inhibition may have deleterious effects on T lymphocyte function. Here, we corroborate the role of oncogenic BRAF in immune evasion by melanoma cells through suppression of MDAs. We show that inhibition of the MAPK pathway with MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitors or a specific inhibitor of BRAF(V600E) in melanoma cell lines and tumor digests results in increased levels of MDAs, which is associated with improved recognition by antigen-specific T lymphocytes. However, treatment with MEK inhibitors impairs T lymphocyte function, whereas T-cell function is preserved after treatment with a specific inhibitor of BRAF(V600E). These findings suggest that immune evasion of melanomas mediated by oncogenic BRAF may be reversed by targeted BRAF inhibition without compromising T-cell function. These findings have important implications for combined kinase-targeted therapy plus immunotherapy for melanoma. Cancer Res; 70(13); 5213-9. (C) 2010 AACR.