Division of Hematology and Oncology, Department of Medicine, Freiburg University Medical Center, Albert Ludwigs University, Hugstetterstr. 55, 79106 Freiburg, Germany.
Cancer Res. 2010 Dec 15;70(24):10170-81. doi: 10.1158/0008-5472.CAN-10-1943.
Clinical studies indicate a role of allogeneic hematopoietic cell transplantation (alloHCT) for patients with refractory or recurrent B-cell lymphoma (BCL) indicative of a graft-versus-tumor effect. However, the relevance of local immunosuppression in the BCL microenvironment by donor-derived regulatory T cells (Treg) after alloHCT is unclear. Therefore, we studied Treg recruitment after alloHCT in different murine BCL models and the impact of lymphoma-derived chemoattractive signals. Luciferase transgenic Tregs accumulated in murine BCL microenvironment and microarray-based analysis of BCL tissues revealed increased expression of CXCL9, CXCL10, and CXCL12. In vivo blocking identified the CXCR4/CXCL12 axis as being critical for Treg attraction toward BCL. In contrast to Tregs, effector T cells displayed low levels of CXCR4 and were not affected by the pharmacologic blockade. Most important, blocking CXCR4 not only reduced Treg migration toward tumor tissue but also enhanced antitumor responses after alloHCT. CXCL12 production was dependent on antigen-presenting cells (APC) located in the lymphoma microenvironment, and their diphtheria-toxin receptor (DTR)-based depletion in CD11c.DTR-Tg mice significantly reduced Treg accumulation within BCL tissue. CXCL12 was also detected in human diffuse, large BCL tissues indicative of its potential clinical relevance. In conclusion, we demonstrate that Tregs are recruited toward BCL after alloHCT by infiltrating host APCs in a CXCL12-dependent fashion. Blocking CXCR4 enhanced antitumor effects and prolonged survival of tumor-bearing mice by reducing local Treg accumulation, indicating that CXCR4 is a potential target to interfere with tumor escape after alloHCT.
临床研究表明，异体造血细胞移植（alloHCT）可用于治疗难治性或复发性 B 细胞淋巴瘤（BCL）患者，这表明移植物抗肿瘤效应的存在。然而，供体来源的调节性 T 细胞（Treg）在 alloHCT 后对 BCL 微环境中的局部免疫抑制的相关性尚不清楚。因此，我们研究了不同的鼠 BCL 模型中 alloHCT 后 Treg 的募集情况以及淋巴瘤来源的趋化信号的影响。荧光素酶转基因 Treg 在鼠 BCL 微环境中聚集，BCL 组织的基于微阵列的分析显示 CXCL9、CXCL10 和 CXCL12 的表达增加。体内阻断鉴定出 CXCR4/CXCL12 轴对于 Treg 向 BCL 的吸引力至关重要。与 Treg 相反，效应 T 细胞显示出低水平的 CXCR4，并且不受药物阻断的影响。最重要的是，阻断 CXCR4 不仅减少了 Treg 向肿瘤组织的迁移，而且增强了 alloHCT 后的抗肿瘤反应。CXCL12 的产生依赖于位于淋巴瘤微环境中的抗原呈递细胞（APC），并且在 CD11c.DTR-Tg 小鼠中基于白喉毒素受体（DTR）的消耗显著减少了 BCL 组织中 Treg 的积累。CXCL12 也在人弥漫性大 BCL 组织中检测到，表明其具有潜在的临床相关性。总之，我们证明 Treg 通过浸润宿主 APC 以 CXCL12 依赖的方式被募集到 alloHCT 后的 BCL 中。阻断 CXCR4 通过减少局部 Treg 积累来增强抗肿瘤效应并延长荷瘤小鼠的存活，表明 CXCR4 是干扰 alloHCT 后肿瘤逃逸的潜在靶点。
