Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade.
Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade.
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DOI：
10.1158/2326-6066.cir-13-0215
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发表时间：
2014-07
影响因子：
10.1
通讯作者：
Wargo JA
中科院分区：
文献类型：
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作者：
Cooper ZA;Juneja VR;Sage PT;Frederick DT;Piris A;Mitra D;Lo JA;Hodi FS;Freeman GJ;Bosenberg MW;McMahon M;Flaherty KT;Fisher DE;Sharpe AH;Wargo JA
BRAF靶向治疗在大多数患者中产生客观缓解，但缓解时间较短（约6个月）。相比之下，免疫检查点抑制剂治疗的反应率较低，但反应往往更持久。BRAF抑制导致患者的肿瘤微环境更有利，CD 8 + T细胞浸润增加，免疫抑制细胞因子减少。免疫调节分子PD-L1的表达也增加，这可能有助于耐药性。基于这些发现，我们假设BRAF靶向治疗可能与PD-1通路阻断协同作用，以增强抗肿瘤免疫力。为了验证这一假设，我们开发了一种BRAF（V600 E）/Pten−/−同基因肿瘤移植免疫活性小鼠模型，其中BRAF抑制导致肿瘤内CD 8 + T细胞密度和细胞因子产生显著增加，与患者中BRAF抑制的作用相似。在该模型中，发现CD 8 + T细胞在BRAF抑制的治疗效果中起关键作用。将抗PD-1或抗PD-L1与BRAF抑制剂一起给药导致反应增强，显著延长存活期和减缓肿瘤生长，以及显著增加肿瘤浸润淋巴细胞的数量和活性。这些结果证明了组合的BRAF靶向治疗和免疫检查点阻断之间的协同作用。虽然结合这两种策略的临床试验正在进行中，但重要的问题仍然存在。使用这种新的黑色素瘤小鼠模型的进一步研究可能会提供治疗见解，包括最佳治疗时机和顺序。
BRAF-targeted therapy results in objective responses in the majority of patients, however the responses are short-lived (~6 months). In contrast, treatment with immune checkpoint inhibitors results in a lower response rate, but the responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8+ T-cell infiltrate and a decrease in immunosuppressive cytokines. There is also increased expression of the immunomodulatory molecule PD-L1, which may contribute to the resistance. Based on these findings, we hypothesized that BRAF-targeted therapy may synergize with the PD-1 pathway blockade to enhance antitumor immunity. To test this hypothesis, we developed a BRAF(V600E)/Pten−/− syngeneic tumor graft immunocompetent mouse model in which BRAF inhibition leads to a significant increase in the intratumoral CD8+ T-cell density and cytokine production, similar to the effects of BRAF inhibition in patients. In this model CD8+ T cells were found to play a critical role in the therapeutic effect of BRAF inhibition. Administration of anti-PD-1 or anti-PD-L1 together with a BRAF inhibitor led to an enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor-infiltrating lymphocytes. These results demonstrate synergy between combined BRAF-targeted therapy and immune checkpoint blockade. Although clinical trials combining these two strategies are ongoing, important questions remain. Further studies using this new melanoma mouse model may provide therapeutic insights, including optimal timing and sequence of therapy.