Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.
Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.
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DOI：
10.1158/0008-5472.can-08-2281
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发表时间：
2009-04-01
期刊：
影响因子：
11.2
通讯作者：
Gajewski TF
中科院分区：
文献类型：
--
作者：
Harlin H;Meng Y;Peterson AC;Zha Y;Tretiakova M;Slingluff C;McKee M;Gajewski TF
尽管经常能检测到循环肿瘤抗原特异性T细胞，无论是自发产生的，还是在主动免疫或过继转移之后，但免疫介导的癌症消退仅发生在少数患者中。一个理论上的限速步骤是效应T细胞是否能成功迁移到转移性肿瘤部位。对一系列转移性黑色素瘤活检样本进行的Affymetrix基因表达谱分析显示，根据是否存在与T细胞相关的转录本，样本存在明显的分类。淋巴细胞的存在与特定趋化因子基因的表达相关。通过蛋白质芯片和/或定量逆转录 - 聚合酶链反应证实，六种趋化因子（CCL2、CCL3、CCL4、CCL5、CXCL9和CXCL10）中的一个子集在含有T细胞的肿瘤中优先表达。在人CD8⁺效应T细胞上发现相应的趋化因子受体上调，并且Transwell迁移实验证实了这些趋化因子中的每一种在体外促进CD8⁺效应细胞迁移的能力。通过趋化因子蛋白质芯片筛选鉴定出了一个产生类似广泛趋化因子阵列的黑色素瘤细胞系子集。当这些黑色素瘤细胞作为异种移植物植入非肥胖糖尿病/严重联合免疫缺陷小鼠体内时，它们能更有效地招募人CD8⁺效应T细胞。用特异性抗体阻断趋化因子抑制了CD8⁺T细胞的迁移。我们的结果表明，一部分黑色素瘤转移灶中关键趋化因子的缺乏可能会限制活化T细胞的迁移，这反过来又可能限制抗肿瘤免疫的有效性。
Despite the frequent detection of circulating tumor antigen–specific T cells, either spontaneously or following active immunization or adoptive transfer, immune-mediated cancer regression occurs only in the minority of patients. One theoretical rate-limiting step is whether effector T cells successfully migrate into metastatic tumor sites. Affymetrix gene expression profiling done on a series of metastatic melanoma biopsies revealed a major segregation of samples based on the presence or absence of T-cell-associated transcripts. The presence of lymphocytes correlated with the expression of defined chemokine genes. A subset of six chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8+ effector T cells, and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8+ effector cells in vitro. Screening by chemokine protein array identified a subset of melanoma cell lines that produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8+ effector T cells when implanted as xenografts in nonobese diabetic/severe combined immunodeficient mice in vivo. Chemokine blockade with specific antibodies inhibited migration of CD8+ T cells. Our results suggest that lack of critical chemokines in a subset of melanoma metastases may limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity.