Constitutive expression and costimulatory function of LIGHT/TNFSF14 on human melanoma cells and melanoma-derived microvesicles
Constitutive expression and costimulatory function of LIGHT/TNFSF14 on human melanoma cells and melanoma-derived microvesicles
复制标题
DOI：
10.1158/0008-5472.can-04-3239
复制
发表时间：
2005-04-15
期刊：
影响因子：
11.2
通讯作者：
Anichini, A
中科院分区：
文献类型：
--
作者：
Mortarini, R;Scarito, A;Anichini, A
肿瘤细胞被认为具有共刺激分子的缺陷表达。然而，在这项研究中，我们发现，人类黑色素瘤细胞表达LIGHT/TNFSF 14，一种T细胞上疱疹病毒进入介体和基质细胞上的β-光毒素受体的配体。在体外，黑色素瘤细胞在细胞内区室中对LIGHT染色，具有弱或阴性的细胞表面表达。然而，LIGHT在从黑素瘤细胞释放的肿瘤衍生的微泡上表达。在体内，LIGHT在转移性病变中被发现，基质细胞上的光敏素β受体表达的程度与肿瘤组织中的“活跃”T细胞浸润显著相关。在具有活跃的T细胞浸润的病变中，肿瘤周围的基质细胞也针对T细胞引诱趋化因子CCL 21染色。尿道内T淋巴细胞经常表达疱疹病毒进入介质，其特征在于分化的表型。淋巴细胞与LIGHT（+）黑色素瘤衍生微泡或甚至与LIGHT（+）黑色素瘤细胞在白细胞介素2存在下共培养共刺激LIGHT依赖性CD 3（+）CD 8（+）T细胞增殖。然而，淋巴细胞与LIGHT（+）微泡在白细胞介素-2存在下共培养也与凋亡反应相关，如CD 3（+）CD 8（+）T细胞与膜联蛋白V结合增加所证实的。这些数据表明，在人黑色素瘤细胞和微泡中组成型表达的LIGHT可能有助于调节T细胞对肿瘤细胞的反应。
Neoplastic cells are thought to have defective expression of costimulatory molecules. However, in this study, we show that human melanoma cells express LIGHT/TNFSF14, a ligand of herpesvirus entry mediator on T cells and of lymphotoxin beta receptor on stromal cells. In vitro, melanoma cells stained for LIGHT in the intracellular compartment, with weak or negative cell surface expression. However, LIGHT was expressed on tumor-derived microvesicles released from melanoma cells. In vivo, LIGHT was found in metastatic lesions, and the extent of lymphotoxin beta receptor expression on the stromal cells was significantly associated with a "brisk" T-cell infiltrate in the neoplastic tissue. In the lesions with a brisk T-cell infiltrate, stromal cells surrounding the tumor also stained for the T-cell attractant chemokine CCL21. The intraturnoral T lymphocytes frequently expressed herpesvirus entry mediator and were characterized by a differentiated phenotype. Coculture of lymphocytes with LIGHT(+) melanoma-derived microvesicles or even with LIGHT(+) melanoma cells in the presence of interleukin-2 costimulated LIGHT-dependent CD3(+)CD8(+) T-cell proliferation. However, lymphocyte coculture with LIGHT(+) microvesicles in the presence of interleukin-2 was also associated with an apoptotic response as documented by increased binding of Annexin V by CD3(+)CD8(+) T cells. These data suggest that LIGHT constitutively expressed in human melanoma cells and microvesicles may contribute to regulate T-cell responses to tumor cells.