Authors' Affiliations: GlaxoSmithKline Vaccines, Rixensart, Belgium.
Cancer Immunol Res. 2014 Apr;2(4):351-60. doi: 10.1158/2326-6066.CIR-13-0181. Epub 2014 Jan 17.
Combination therapy with BRAF and MEK inhibition is currently in clinical development for the treatment of BRAF-mutated malignant melanoma. BRAF inhibitors are associated with enhanced antigen-specific T-lymphocyte recognition in vivo. Consequently, BRAF inhibition has been proposed as proimmunogenic and there has been considerable enthusiasm for combining BRAF inhibition with immunotherapy. MEK inhibitors inhibit ERK phosphorylation regardless of BRAF mutational status and have been reported to impair T-lymphocyte and modulate dendritic cell function. In this study, we investigate the effects on isolated T lymphocytes and monocyte-derived dendritic cells (moDC) of a MEK (trametinib) and BRAF (dabrafenib) inhibitor combination currently being evaluated in a randomized controlled clinical trial. The effects of dabrafenib and trametinib, alone and in combination, were studied on isolated normal T lymphocytes and moDCs. Lymphocyte viability, together with functional assays including proliferation, cytokine production, and antigen-specific expansion, were assessed. MoDC phenotype in response to lipopolysaccharide stimulation was evaluated by flow cytometry, as were effects on antigen cross-presentation. Dabrafenib did not have an impact on T lymphocytes or moDCs, whereas trametinib alone or in combination with dabrafenib suppressed T-lymphocyte proliferation, cytokine production, and antigen-specific expansion. However, no significant decrease in CD4(+) or CD8(+) T-lymphocyte viability was observed following kinase inhibition. MoDC cross-presentation was suppressed in association with enhanced maturation following combined inhibition of MEK and BRAF. The results of this study demonstrate that MEK inhibition, alone or in combination with BRAF inhibition, can modulate immune cell function, and further studies in vivo will be required to evaluate the potential clinical impact of these findings.
BRAF 和 MEK 抑制的联合治疗目前正在临床开发中，用于治疗 BRAF 突变型恶性黑色素瘤。BRAF 抑制剂与体内增强的抗原特异性 T 淋巴细胞识别有关。因此，BRAF 抑制被认为具有免疫原性，并且人们对将 BRAF 抑制与免疫疗法相结合产生了浓厚的兴趣。MEK 抑制剂抑制 ERK 磷酸化，而不考虑 BRAF 突变状态，并已被报道会损害 T 淋巴细胞并调节树突状细胞功能。在这项研究中，我们研究了目前正在一项随机对照临床试验中评估的 MEK（曲美替尼）和 BRAF（达拉非尼）抑制剂联合对分离的 T 淋巴细胞和单核细胞衍生的树突状细胞（moDC）的影响。研究了达拉非尼和曲美替尼单独和联合使用对分离的正常 T 淋巴细胞和 moDC 的影响。评估了淋巴细胞活力以及包括增殖、细胞因子产生和抗原特异性扩增在内的功能测定。通过流式细胞术评估 moDC 对脂多糖刺激的表型，以及对抗原交叉呈递的影响。达拉非尼对 T 淋巴细胞或 moDC 没有影响，而曲美替尼单独或与达拉非尼联合抑制 T 淋巴细胞增殖、细胞因子产生和抗原特异性扩增。然而，在激酶抑制后，没有观察到 CD4(+)或 CD8(+)T 淋巴细胞活力的显著下降。MEK 和 BRAF 的联合抑制与增强的成熟相关，抑制了 moDC 的交叉呈递。这项研究的结果表明，MEK 抑制，单独或与 BRAF 抑制联合使用，可调节免疫细胞功能，需要进一步的体内研究来评估这些发现的潜在临床影响。
