Tumor progression despite massive influx of activated CD8+ T cells in a patient with malignant melanoma ascites
Tumor progression despite massive influx of activated CD8+ T cells in a patient with malignant melanoma ascites
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DOI：
10.1007/s00262-005-0118-2
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发表时间：
2006-10-01
影响因子：
5.8
通讯作者：
Gajewski, Thomas F.
中科院分区：
文献类型：
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作者：
Harlin, Helena;Kuna, Todd V.;Gajewski, Thomas F.
虽然黑色素瘤肿瘤通常表达可被T细胞识别的抗原，但免疫介导的肿瘤排斥是罕见的。在许多情况下，尽管存在高频率的循环肿瘤抗原特异性T细胞，但这表明T细胞引发下游的肿瘤抗性代表了关键屏障。直接从黑色素瘤肿瘤微环境中分析T细胞，以及微环境本身的性质，对于理解肿瘤逃逸的关键下游机制至关重要。在目前的报告中，我们研究了转移性黑色素瘤和大量恶性腹水患者的肿瘤相关淋巴细胞。腹水显示大量表达常见黑素瘤抗原的肿瘤细胞，并保留I类MHC和抗原加工机制的表达。腹水中含有趋化因子CCL 10、CCL 15和CCL 18，这些趋化因子与大量活化T细胞的流入有关，包括识别HLA-A2四聚体复合物的CD 8（+）T细胞，该四聚体复合物具有Melan-A和NA 17-A的肽。然而，观察到这些肿瘤抗原特异性T细胞的几个功能缺陷，包括响应肽脉冲APC或自体肿瘤细胞的IFN-γ产生不良，以及缺乏穿孔素表达。虽然这些缺陷是T细胞固有的，但我们也观察到大量的CD 4（+）CD 25（+）FoxP 3（+）T细胞，以及FoxP 3、IL-10、PD-L1/B7-H1和吲哚胺-2，3-双加氧酶（IDO）的转录物。我们的观察结果表明，尽管大量活化的CD 8（+）T细胞被募集到肿瘤微环境中，但T细胞低反应性和额外的负调控机制可能限制抗肿瘤免疫应答的效应期。
Although melanoma tumors usually express antigens that can be recognized by T cells, immune-mediated tumor rejection is rare. In many cases this is despite the presence of high frequencies of circulating tumor antigen-specific T cells, suggesting that tumor resistance downstream from T cell priming represents a critical barrier. Analyzing T cells directly from the melanoma tumor microenvironment, as well as the nature of the microenvironment itself, is central for understanding the key downstream mechanisms of tumor escape. In the current report we have studied tumor-associated lymphocytes from a patient with metastatic melanoma and large volume malignant ascites. The ascites fluid showed abundant tumor cells that expressed common melanoma antigens and retained expression of class I MHC and antigen processing machinery. The ascites fluid contained the chemokines CCL10, CCL15, and CCL18 which was associated with a large influx of activated T cells, including CD8(+) T cells recognizing HLA-A2 tetramer complexes with peptides from Melan-A and NA17-A. However, several functional defects of these tumor antigen-specific T cells were seen, including poor production of IFN-gamma in response to peptide-pulsed APC or autologous tumor cells, and lack of expression of perforin. Although these defects were T cell intrinsic, we also observed abundant CD4(+)CD25(+)FoxP3(+) T cells, as well as transcripts for FoxP3, IL-10, PD-L1/B7-H1, and indoleamine-2,3-dioxygenase (IDO). Our observations suggest that, despite recruitment of large numbers of activated CD8(+) T cells into the tumor microenvironment, T cell hyporesponsiveness and additional negative regulatory mechanisms can limit the effector phase of the anti-tumor immune response.