Functional expression cloning identifies COX-2 as a suppressor of antigen-specific cancer immunity.
Functional expression cloning identifies COX-2 as a suppressor of antigen-specific cancer immunity.
复制标题
功能表达克隆将COX-2鉴定为抗原特异性癌症免疫的抑制剂。
DOI：
10.1038/cddis.2014.531
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发表时间：
2014-12-11
影响因子：
9
通讯作者：
Schuler M
中科院分区：
文献类型：
--
作者：
Göbel C;Breitenbuecher F;Kalkavan H;Hähnel PS;Kasper S;Hoffarth S;Merches K;Schild H;Lang KS;Schuler M
免疫监视和抗原特异性癌症免疫疗法的功效同样取决于靶向癌症抗原的持续免疫应答的激活和癌细胞对免疫效应机制的易感性。利用功能性表达克隆和T细胞受体（TCR）转基因小鼠，我们已经鉴定了环氧合酶2/内过氧化物合酶2（考克斯-2）作为抵抗活化的抗原特异性T细胞诱导的细胞毒性的抵抗因子。表达考克斯-2，但不表达无催化活性的考克斯-2突变体，当与来自St 42 Rag 2 −/−小鼠的淋巴细胞共培养时，E1 A转化的小鼠癌细胞的克隆形成存活率增加，所述St 42 Rag 2 −/−小鼠携带针对E1 A表位的转基因TCR。在免疫缺陷小鼠中建立的表达考克斯-2的肿瘤对体内TCR转基因淋巴细胞的过继免疫治疗较不敏感。此外，TCR转基因小鼠中考克斯-2阳性肿瘤细胞的免疫监视效率较低。选择性考克斯-2抑制剂塞来昔布治疗可有效抑制免疫活性小鼠中显示内源性考克斯-2高表达的小鼠MC-GP肿瘤的生长。从机制上讲，考克斯-2表达减弱了抗原特异性T细胞暴露于其各自细胞靶点的干扰素-γ释放，并增加了肿瘤细胞白细胞介素-4和吲哚胺2，3-双加氧酶的表达。添加干扰素-γ使表达考克斯-2的癌细胞对抗原特异性T细胞的肿瘤抑制敏感。总之，考克斯-2，这是经常诱导结直肠癌，有助于免疫逃避和抵抗抗原特异性癌症免疫治疗的局部抑制T细胞效应功能。
The efficacy of immune surveillance and antigen-specific cancer immunotherapy equally depends on the activation of a sustained immune response targeting cancer antigens and the susceptibility of cancer cells to immune effector mechanisms. Using functional expression cloning and T-cell receptor (TCR) transgenic mice, we have identified cyclooxygenase 2/prostaglandin-endoperoxide synthase 2 (COX-2) as resistance factor against the cytotoxicity induced by activated, antigen-specific T cells. Expressing COX-2, but not a catalytically inactive COX-2 mutant, increased the clonogenic survival of E1A-transformed murine cancer cells when cocultured with lymphocytes from St42Rag2−/− mice harboring a transgenic TCR directed against an E1A epitope. COX-2 expressing tumors established in immune-deficient mice were less susceptible to adoptive immunotherapy with TCR transgenic lymphocytes in vivo. Also, immune surveillance of COX-2-positive tumor cells in TCR transgenic mice was less efficient. The growth of murine MC-GP tumors, which show high endogenous COX-2 expression, in immunocompetent mice was effectively suppressed by treatment with a selective COX-2 inhibitor, celecoxib. Mechanistically, COX-2 expression blunted the interferon-gamma release of antigen-specific T cells exposed to their respective cellular targets, and increased the expression of interleukin-4 and indoleamine 2,3-dioxygenase by tumor cells. Addition of interferon-gamma sensitized COX-2 expressing cancer cells to tumor suppression by antigen-specific T cells. In conclusion, COX-2, which is frequently induced in colorectal cancer, contributes to immune evasion and resistance to antigen-specific cancer immunotherapy by local suppression of T-cell effector functions.