Hanson Erica M, Clements Virginia K, Sinha Pratima, Ilkovitch Dan, Ostrand-Rosenberg Suzanne
Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250, USA.
J Immunol. 2009 Jul 15;183(2):937-44. doi: 10.4049/jimmunol.0804253. Epub 2009 Jun 24.
Effective cell-mediated antitumor immunity requires the activation of tumor-reactive T cells and the trafficking of activated T cells to tumor sites. These processes involve the extravasation of lymphocytes from the blood and lymphatics, and their homing to lymph nodes and tumors. L-selectin (CD62L) is an important molecule in these processes. It directs naive lymphocytes to peripheral lymph nodes where they become activated and it traffics naive lymphocytes to inflammatory environments, such as tumors. Individuals with advanced cancer are immune suppressed due to myeloid-derived suppressor cells (MDSC), a population of immature myeloid cells that accumulate to high levels in response to tumor-secreted and proinflammatory factors. We now demonstrate that the reduction in T cell levels of L-selectin that is commonly seen in individuals with cancer inversely correlates with MDSC levels. Three lines of evidence demonstrate that MDSC directly down-regulate L-selectin on naive T cells: 1) naive T cells cocultured with tumor-induced MDSC have reduced L-selectin; 2) T cells in tumor-free aged mice with elevated levels of MDSC have reduced L-selectin, and 3) peritoneal exudate T cells of tumor-free mice treated with plasminogen activator urokinase to elevate MDSC have reduced levels of L-selectin. MDSC are likely to down-regulate L-selectin through their plasma membrane expression of ADAM17 (a disintegrin and metalloproteinase domain 17), an enzyme that cleaves the ectodomain of L-selectin. Therefore, MDSC down-regulate L-selectin levels on naive T cells, decreasing their ability to home to sites where they would be activated. This is another mechanism by which MDSC inhibit antitumor immunity.
有效的细胞介导抗肿瘤免疫需要激活肿瘤反应性T细胞，并将活化的T细胞运输到肿瘤部位。这些过程涉及淋巴细胞从血液和淋巴管外渗，以及它们归巢至淋巴结和肿瘤。L-选择素（CD62L）是这些过程中的一个重要分子。它引导初始淋巴细胞至外周淋巴结，在那里它们被激活，并且它将初始淋巴细胞运输至炎症环境，如肿瘤。患有晚期癌症的个体由于髓系来源的抑制细胞（MDSC）而免疫抑制，MDSC是一群未成熟的髓系细胞，其因肿瘤分泌的因子和促炎因子而积累至高水平。我们现在证明，在癌症患者中常见的T细胞L-选择素水平降低与MDSC水平呈负相关。三条证据表明MDSC直接下调初始T细胞上的L-选择素：1）与肿瘤诱导的MDSC共培养的初始T细胞L-选择素减少；2）MDSC水平升高的无肿瘤老龄小鼠中的T细胞L-选择素减少，以及3）用纤溶酶原激活物尿激酶处理以升高MDSC的无肿瘤小鼠的腹腔渗出液T细胞L-选择素水平降低。MDSC可能通过其质膜表达的ADAM17（一种解整合素和金属蛋白酶结构域17）下调L-选择素，ADAM17是一种切割L-选择素胞外结构域的酶。因此，MDSC下调初始T细胞上的L-选择素水平，降低它们归巢至可被激活部位的能力。这是MDSC抑制抗肿瘤免疫的另一种机制。
