Selective BRAF Inhibitors Induce Marked T-cell Infiltration into Human Metastatic Melanoma
Selective BRAF Inhibitors Induce Marked T-cell Infiltration into Human Metastatic Melanoma
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DOI：
10.1158/1078-0432.ccr-11-2479
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发表时间：
2012-03-01
影响因子：
11.5
通讯作者：
Scolyer, Richard A.
中科院分区：
文献类型：
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作者：
Wilmott, James S.;Long, Georgina V.;Scolyer, Richard A.
目的：为了评价用强效突变BRAF抑制剂GSK 2118436或维罗非尼（PLX 4720）治疗对治疗前后采集的组织中转移性黑素瘤的免疫应答的影响。三十-在BRAF开始前即刻和开始后约7天，从15名患有不可切除的美国癌症联合委员会III期或IV期黑色素瘤的患者中收集了7份肿瘤活检抑制剂治疗和肿瘤进展时。使用CD 8、CD 4、CD 20、CD 1a和颗粒酶B的特异性抗体对活检组织进行免疫组织化学染色。结果：BRAF抑制剂治疗后，CD 4（+）和CD 8（+）淋巴细胞的肿瘤浸润显着增加（均rho = 0.015）。在BRAF治疗后的活检组织中，CD 8（+）和颗粒酶B表达淋巴细胞的肿瘤浸润程度之间存在相关性（r = 0.690和rho = 0.013）。肿瘤内CD 8（+）淋巴细胞表达的增加与治疗后活检中肿瘤大小的减小和坏死的增加相关（r =-0.793，rho = 0.011; r = 0.761，rho = 0.004）。肿瘤的增加-通过BRAF抑制剂治疗诱导的浸润淋巴细胞为进行BRAF抑制剂与免疫治疗相结合的试验提供了强有力的支持，临床反应。临床癌症研究; 18（5）; 1386-94。（C）2011年《非洲标准化评论》。
Purpose: To evaluate the effects of treatment with the potent mutant BRAF inhibitors GSK2118436 or vemurafenib (PLX4720) on immune responses to metastatic melanoma in tissues taken before and after treatment.Experimental Design: Thirty-seven tumor biopsies were collected from 15 patients with unresectable American Joint Committee on Cancer stage III or IV melanoma immediately before and approximately 7 days after the commencement of BRAF inhibitor treatment and at the time of tumor progression. Immunohistochemical staining was carried out on the biopsies using specific antibodies for CD8, CD4, CD20, CD1a, and Granzyme B.Results: Tumor infiltration by CD4(+) and CD8(+) lymphocytes increased markedly following BRAF inhibitor treatment (both rho = 0.015). There was a correlation between the degree of tumor infiltration by CD8(+) and Granzyme B-expressing lymphocytes in post-BRAF inhibitor-treated biopsies (r = 0.690 and rho = 0.013). Increased intratumoral CD8(+) lymphocyte expression was correlated with a reduction in tumor size and an increase in necrosis in posttreatment biopsies (r = -0.793, rho = 0.011; and r = 0.761, rho = 0.004, respectively).Conclusions: The increase in tumor-infiltrating lymphocytes induced by treatment with BRAF inhibitors provides strong support for conducting trials that combine BRAF inhibitors with immunotherapy in the hope of prolonging clinical responses. Clin Cancer Res; 18(5); 1386-94. (C)2011 AACR.