BRAF inhibition is associated with increased clonality in tumor-infiltrating lymphocytes.
BRAF inhibition is associated with increased clonality in tumor-infiltrating lymphocytes.
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DOI：
10.4161/onci.26615
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发表时间：
2013-10-01
期刊：
影响因子：
7.2
通讯作者：
Wargo JA
中科院分区：
文献类型：
--
作者：
Cooper ZA;Frederick DT;Juneja VR;Sullivan RJ;Lawrence DP;Piris A;Sharpe AH;Fisher DE;Flaherty KT;Wargo JA
针对转移性黑色素瘤的BRAF靶向治疗已经取得了重大进展。然而，大多数接受BRAF抑制剂（BRAFi）的患者在一年内表现出疾病进展。我们最近已经表明，用BRAFi治疗的黑素瘤患者表现出黑素瘤相关抗原和CD 8+肿瘤浸润淋巴细胞对治疗的反应增加。为了表征这种T细胞浸润，我们分析了BRAFi开始前和10-14天后获得的肿瘤活检组织中重排T细胞受体（TCR）β链编码基因的互补决定区3（CDR 3）。我们观察到8例接受BRAFi的患者中有7例肿瘤浸润淋巴细胞的克隆性增加，克隆性增加了21%，具有统计学显著性。在BRAFi处理开始后检测到的超过80%的单个T细胞克隆是新克隆。有趣的是，肿瘤浸润与临床反应的比较显示，在施用BRAFi后具有高比例的预先存在的显性克隆的患者比在BRAFi后具有低比例的这种预先存在的显性克隆的患者对治疗的反应更好。这些数据表明，尽管黑色素瘤患者中BRAF的抑制导致新淋巴细胞的肿瘤浸润，但对治疗的反应似乎与预先存在的肿瘤浸润T细胞克隆群的存在有关。
There have been significant advances with regard to BRAF-targeted therapies against metastatic melanoma. However, the majority of patients receiving BRAF inhibitors (BRAFi) manifest disease progression within a year. We have recently shown that melanoma patients treated with BRAFi exhibit an increase in melanoma-associated antigens and in CD8+ tumor-infiltrating lymphocytes in response to therapy. To characterize such a T-cell infiltrate, we analyzed the complementarity-determining region 3 (CDR3) of rearranged T-cell receptor (TCR) β chain-coding genes in tumor biopsies obtained before the initiation of BRAFi and 10–14 d later. We observed an increase in the clonality of tumor-infiltrating lymphocytes in 7 of 8 patients receiving BRAFi, with a statistically significant 21% aggregate increase in clonality. Over 80% of individual T-cell clones detected after initiation of BRAFi treatment were new clones. Interestingly, the comparison of tumor infiltrates with clinical responses revealed that patients who had a high proportion of pre-existing dominant clones after the administration of BRAFi responded better to therapy than patients who had a low proportion of such pre-existing dominant clones following BRAFi. These data suggest that although the inhibition of BRAF in melanoma patients results in tumor infiltration by new lymphocytes, the response to treatment appears to be related to the presence of a pre-existing population of tumor-infiltrating T-cell clones.