MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells.
MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells.
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DOI：
10.1186/1476-4598-9-11
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发表时间：
2010-01-20
期刊：
影响因子：
37.3
通讯作者：
Patankar MS
中科院分区：
文献类型：
--
作者：
Gubbels JA;Felder M;Horibata S;Belisle JA;Kapur A;Holden H;Petrie S;Migneault M;Rancourt C;Connor JP;Patankar MS
癌细胞利用多种机制逃避免疫检测和攻击。有效的免疫检测在很大程度上依赖于免疫突触的形成，这需要免疫细胞和它们的目标之间的密切接触。在这里，我们发现MUC16，一种在卵巢肿瘤细胞表面表达的高度糖基化的3-5百万Da粘蛋白，抑制NK细胞和卵巢肿瘤靶点之间免疫突触的形成。我们的研究结果表明，muc16介导的免疫突触形成抑制是卵巢肿瘤逃避免疫识别的有效机制。低水平MUC16的表达与卵巢肿瘤细胞和原代naïve NK细胞之间共轭物和激活免疫突触的数量增加密切相关。MUC16敲低的卵巢肿瘤细胞比表达MUC16的对照组更容易被原代NK细胞溶解。这种增加的裂解不是由于激活受体DNAM-1和NKG2D的配体表达水平的差异。NK细胞白血病细胞系（NKL）不表达KIRs，但DNAM-1和NKG2D呈阳性，也比表达MUC16的对照组更有效地结合和裂解MUC16敲低的细胞。在NKL攻击下存活的肿瘤细胞表达更高水平的MUC16，表明MUC16低靶点选择性裂解。与从未暴露于效应物的靶细胞相比，NKL抗性肿瘤细胞上较高的csMUC16水平与更多的裂解保护相关。MUC16是肿瘤标志物CA125的载体，先前已被证明可促进卵巢肿瘤转移并抑制NK细胞介导的肿瘤靶点裂解。我们现在的数据表明，表达MUC16的卵巢癌细胞不被NK细胞识别。MUC16提供的免疫保护可能导致卵巢癌细胞的选择性存活，这些细胞在腹腔内转移和克服抗肿瘤先天免疫反应方面更有效。
Cancer cells utilize a variety of mechanisms to evade immune detection and attack. Effective immune detection largely relies on the formation of an immune synapse which requires close contact between immune cells and their targets. Here, we show that MUC16, a heavily glycosylated 3-5 million Da mucin expressed on the surface of ovarian tumor cells, inhibits the formation of immune synapses between NK cells and ovarian tumor targets. Our results indicate that MUC16-mediated inhibition of immune synapse formation is an effective mechanism employed by ovarian tumors to evade immune recognition. Expression of low levels of MUC16 strongly correlated with an increased number of conjugates and activating immune synapses between ovarian tumor cells and primary naïve NK cells. MUC16-knockdown ovarian tumor cells were more susceptible to lysis by primary NK cells than MUC16 expressing controls. This increased lysis was not due to differences in the expression levels of the ligands for the activating receptors DNAM-1 and NKG2D. The NK cell leukemia cell line (NKL), which does not express KIRs but are positive for DNAM-1 and NKG2D, also conjugated and lysed MUC16-knockdown cells more efficiently than MUC16 expressing controls. Tumor cells that survived the NKL challenge expressed higher levels of MUC16 indicating selective lysis of MUC16low targets. The higher csMUC16 levels on the NKL resistant tumor cells correlated with more protection from lysis as compared to target cells that were never exposed to the effectors. MUC16, a carrier of the tumor marker CA125, has previously been shown to facilitate ovarian tumor metastasis and inhibits NK cell mediated lysis of tumor targets. Our data now demonstrates that MUC16 expressing ovarian cancer cells are protected from recognition by NK cells. The immune protection provided by MUC16 may lead to selective survival of ovarian cancer cells that are more efficient in metastasizing within the peritoneal cavity and also at overcoming anti-tumor innate immune responses.
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影响因子：
6.4
作者：
Belisle, Jennifer A.;Gubbels, Jennifer A. A.;Patankar, Manish S.
通讯作者：
Patankar, Manish S.
影响因子：
11.2
作者：
Carlsten, Mattias;Bjorkstrom, Niklas K.;Malmberg, Karl Johan
通讯作者：
Malmberg, Karl Johan
DOI：
10.1083/jcb.200707199
发表时间：
2007-11-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ilani T;Khanna C;Zhou M;Veenstra TD;Bretscher A
通讯作者：
Bretscher A
影响因子：
4.4
作者：
Blalock, Timothy D.;Spurr-Michaud, Sandra J.;Gipson, Ilene K.
通讯作者：
Gipson, Ilene K.
影响因子：
7.5
作者：
Krzewski K;Strominger JL
通讯作者：
Strominger JL