T-Cell Trafficking Facilitated by High Endothelial Venules Is Required for Tumor Control after Regulatory T-Cell Depletion
T-Cell Trafficking Facilitated by High Endothelial Venules Is Required for Tumor Control after Regulatory T-Cell Depletion
复制标题
DOI：
10.1158/0008-5472.can-12-1912
复制
发表时间：
2012-11-01
期刊：
影响因子：
11.2
通讯作者：
Gallimore, Awen M.
中科院分区：
文献类型：
--
作者：
Hindley, James P.;Jones, Emma;Gallimore, Awen M.
肿瘤中免疫阻断的演变限制了成功的抗肿瘤免疫，但这一过程的机制尚未完全了解。调节性T细胞（Treg）是一种抑制过度炎症和自身反应性反应的T细胞亚群，其耗竭可激活肿瘤特异性T细胞。然而，癌症免疫治疗研究表明，活化的淋巴细胞浸润肿瘤的持续失败仍然是一个根本问题。在评估这个问题时，我们发现尽管Treg耗尽后T细胞活化和增殖增加，但与肿瘤生长率没有显著相关性。相反，低肿瘤生长率和T细胞浸润程度之间存在高度显著的相关性。进一步的分析显示，低肿瘤生长率，高T细胞浸润，高内皮微静脉（HEV）的存在之间的总一致性。HEV是通常在次级淋巴组织中发现的血管，在那里它们专门用于淋巴细胞募集。因此，我们的研究结果表明，Treg耗竭可能会促进HEV新生，促进淋巴细胞浸润增加和肿瘤组织的破坏。这些发现是重要的，因为它们指出了迄今为止尚未确定的TdR作用，对其的操纵可能会改进更有效的癌症免疫治疗策略。Cancer Res; 72（21）; 5473-82.（C）2012年AACR。
The evolution of immune blockades in tumors limits successful antitumor immunity, but the mechanisms underlying this process are not fully understood. Depletion of regulatory T cells (Treg), a T-cell subset that dampens excessive inflammatory and autoreactive responses, can allow activation of tumor-specific T cells. However, cancer immunotherapy studies have shown that a persistent failure of activated lymphocytes to infiltrate tumors remains a fundamental problem. In evaluating this issue, we found that despite an increase in T-cell activation and proliferation following Treg depletion, there was no significant association with tumor growth rate. In contrast, there was a highly significant association between low tumor growth rate and the extent of T-cell infiltration. Further analyses revealed a total concordance between low tumor growth rate, high T-cell infiltration, and the presence of high endothelial venules (HEV). HEV are blood vessels normally found in secondary lymphoid tissue where they are specialized for lymphocyte recruitment. Thus, our findings suggest that Treg depletion may promote HEV neogenesis, facilitating increased lymphocyte infiltration and destruction of the tumor tissue. These findings are important as they point to a hitherto unidentified role of Tregs, the manipulation of which may refine strategies for more effective cancer immunotherapy. Cancer Res; 72(21); 5473-82. (C)2012 AACR.