研究癌細(xì)胞如何逃避免疫系統(tǒng)攻擊的研究人員發(fā)現(xiàn)：某些腫瘤的環(huán)加氧酶2(cyclooxygenase-2, COX-2)基因過(guò)度表達(dá)，防止樹突狀細(xì)胞參與Th1炎性反應(yīng)并導(dǎo)致它們轉(zhuǎn)換進(jìn)入Tr1免疫抑制模式。

在正常情況下，樹突狀細(xì)胞誘導(dǎo)生成白介素12(interleukin-12, IL-12)，IL12促使CD4+T淋巴細(xì)胞啟動(dòng)T輔助細(xì)胞1(T help1, Th1)型炎癥反應(yīng)。但是，在2004年10月1日出版的《免疫學(xué)期刊》(the Journal of Immunology)的一篇文章中， Cedars-Sinai醫(yī)學(xué)中心(Los Angeles, CA, USA; www.cedars-sinai.edu/mdnsi) Maxine Dunitz神經(jīng)外科研究所的研究人員報(bào)道說(shuō)：COX-2過(guò)度表達(dá)可以調(diào)節(jié)樹突狀細(xì)胞的生物學(xué)行為。

當(dāng)樹突狀細(xì)胞暴露于癌細(xì)胞的時(shí)候，由于癌細(xì)胞過(guò)度表達(dá)COX-2導(dǎo)致前列腺素E2水平升高，樹突狀細(xì)胞促使白介素10以及轉(zhuǎn)化生長(zhǎng)因子beta過(guò)度生成，而不是正常的白介素12生成。這兩種物質(zhì)觸發(fā)Tr1調(diào)節(jié)反應(yīng)，導(dǎo)致淋巴細(xì)胞對(duì)腫瘤抗原發(fā)生耐受。

Maxine Dunitz神經(jīng)外科研究所《綜合腦組織腫瘤項(xiàng)目》合作主任、高級(jí)作者John S. Yu博士說(shuō)：“腫瘤組織通過(guò)表達(dá)COX-2從而使它們逃避免疫系統(tǒng)的識(shí)別。通過(guò)使用COX-2抑制劑，可以使這些腫瘤容易被免疫系統(tǒng)發(fā)現(xiàn)，從而利于免疫系統(tǒng)摧毀這些腫瘤。這些令人振奮的發(fā)現(xiàn)之一是：從一例神經(jīng)膠質(zhì)母細(xì)胞瘤患者血流中分離出的T輔助細(xì)胞，對(duì)該患者的神經(jīng)膠質(zhì)瘤細(xì)胞產(chǎn)生明顯的調(diào)節(jié)反應(yīng)。這點(diǎn)提示了在 惡性神經(jīng)膠質(zhì)瘤患者的循環(huán)T細(xì)胞中存在調(diào)節(jié)偏差。

COX-2 Helps Cancer Cells Avoid Immune Attack
 
Researchers studying how cancer cells avoid attack by the immune system have found that overexpression of the gene for cyclooxygenase-2 (COX-2) by certain tumors prevents dendritic cells from staging a Th1 inflammatory response and causes them to shift into a Tr1 immunosuppressive mode.

Normally, dendritic cells induce the production of interleukin-12 (IL-12), which prompts CD4+ T lymphocytes to launch a T helper type 1 (Th1) inflammatory response. However, in the current study published in the October 1, 2004, issue of the Journal of Immunology, investigators at the Maxine Dunitz Neurosurgical Institute of Cedars-Sinai Medical Center (Los Angeles, CA, USA; www.cedars-sinai.edu/mdnsi) reported that overexpression of COX-2 modified dendritic cell behavior.

When dendritic cells were exposed to cancer cells whose COX-2 overexpression caused elevated levels of prostaglandin E2, the dendritic cells prompted the overproduction of interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) instead of inducing the production of interleukin-12 (IL-12). These two substances triggered a Trl regulatory response that caused lymphocytes to be tolerant of tumor cell antigens.

Senior author Dr. John S. Yu, co-director of the comprehensive brain tumor program at the Maxine Dunitz Neurosugical Institute, said, “COX-2 expression by tumors may make them invisible to the immune system. By using COX-2 inhibitors, these tumors may become more detectable and therefore more vulnerable to destruction by the immune system. One of the intriguing findings was that helper cells isolated from the bloodstream of a glioblastoma patient predominantly displayed a regulatory response against the patient’s glioma cells. This points to the existence of an underlying regulatory bias in the circulating T cells of patients with malignant glioma."