Role of T regulatory suppression in autoimmunity and cancer

T 调节抑制在自身免疫和癌症中的作用

• 批准号: 8157403
• 负责人: JOOST J OPPENHEIM
• 金额: $ 46.76万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8157403
• 关键词: Autoimmunity; Malignant Neoplasms; Role

Our studies of Tregs have revealed that TNF by acting on the TNFR2 receptor, which is highly expressed by Tregs, unexpectedly results in their proliferative expansion and functional activation both in mice and in man. In view of the well known proinflammatory effects of TNF, our data showing that TNF in a more delayed manner can also down-regulate immune responses is rather surprising. One clarification of these contradictory effects of TNF is based on our data showing that TNF by activating Teffector cells also induces them to express TNFR2 and to become more resistant to the suppressive effects of Tregs. Thus, activated T cells at inflammatory sites or in autoimmune status can prevail over the suppressive effects of Tregs. However, as inflammation subsides in healing wounds or in noninflamed tumors Tregs prevail. Most tumor infiltrating T cells (TIL's) actually express TNFR2 and are activated by tumor-derived TNF to be even more immunosuppressive than Tregs in peripheral lymphoid tissues. Suppression of Tregs should enable more effect host anti-tumor responses to become evident. Consequently, our preliminary results show that anti-TNF reduced the growth of mouse Lewis lung and breast (4T1) tumors. Thus, by identifying better means of countering Tregs, we may be able to enhance antitumor responses to tumor vaccines.

我们对Tregs的研究表明，肿瘤坏死因子通过作用于Tregs高表达的TNFR2受体，意外地导致它们在小鼠和人类体内的增殖扩张和功能激活。鉴于众所周知的肿瘤坏死因子的促炎作用，我们的数据显示，肿瘤坏死因子以更延迟的方式也可以下调免疫反应，这是相当令人惊讶的。对肿瘤坏死因子这些相互矛盾的影响的一种澄清是基于我们的数据，即通过激活T效应细胞也诱导它们表达TNFR2，并对Tregs的抑制作用变得更具抵抗力。因此，炎症部位或自身免疫状态下的活化T细胞可以战胜Tregs的抑制作用。然而，随着炎症在愈合的伤口或非炎症的肿瘤中消退，Tregs占上风。大多数肿瘤浸润性T细胞(TIL)实际上表达TNFR2，并被肿瘤来源的TNF激活，甚至比外周淋巴组织中的Tregs具有更强的免疫抑制作用。抑制Tregs应能使更有效的宿主抗肿瘤反应变得明显。因此，我们的初步结果表明，抗肿瘤坏死因子减少了小鼠Lewis肺癌和乳腺(4T1)肿瘤的生长。因此，通过寻找更好的对抗Tregs的方法，我们可能能够增强对肿瘤疫苗的抗肿瘤反应。