Cho John S, Hsu Jeffrey V, Morrison Sherie L
Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, BSRB 247, 615 Charles E. Young Dr. South, Los Angeles, CA 90095-1570, USA.
Cancer Immunol Immunother. 2009 Jul;58(7):1057-69. doi: 10.1007/s00262-008-0622-2. Epub 2008 Nov 19.
The systemic administration of an agonist antibody against glucocorticoid-induced tumor necrosis factor receptor related (GITR) protein has been shown to be effective in overcoming immune tolerance and promoting tumor rejection in a variety of murine tumor models. However, little is known regarding the functional consequence of ligation of GITR with its natural ligand (GITR-L) in the context of regulatory T cell (Treg) suppression in vivo. To determine the mechanism of GITR-L action in vivo, we generated a panel of tumor cell clones that express varying levels of GITR-L. The ectopic expression of GITR-L on the tumor cell surface was sufficient to enhance anti-tumor immunity and delay tumor growth in syngeneic BALB/c mice. Within the range examined, the extent of anti-tumor activity in vivo did not correlate with the level of GITR-L expression, as all clones tested exhibited a similar delay in tumor growth. The localized expression of GITR-L on tumor cells led to a significant increase in CD8+ T cell infiltration compared to the levels seen in control tumors. The increased proportion of CD8+ T cells was only observed locally at the tumor site and was not seen in the tumor draining lymph node. Depletion studies showed that CD8+ T cells, but not CD4+ T cells, were required for GITR-L mediated protection against tumor growth. These studies demonstrate that signaling between GITR-L and GITR in the tumor microenvironment promotes the infiltration of CD8+ T cells, which are essential for controlling tumor growth.
在多种小鼠肿瘤模型中，全身性给予抗糖皮质激素诱导的肿瘤坏死因子受体相关（GITR）蛋白的激动剂抗体已被证明可有效克服免疫耐受并促进肿瘤排斥。然而，在体内调节性T细胞（Treg）抑制的背景下，关于GITR与其天然配体（GITR-L）结合的功能后果知之甚少。为了确定GITR-L在体内的作用机制，我们构建了一组表达不同水平GITR-L的肿瘤细胞克隆。肿瘤细胞表面异位表达GITR-L足以增强同基因BALB/c小鼠的抗肿瘤免疫力并延缓肿瘤生长。在所检测的范围内，体内抗肿瘤活性的程度与GITR-L表达水平无关，因为所有测试的克隆在肿瘤生长方面均表现出相似的延迟。与对照肿瘤相比，肿瘤细胞上GITR-L的局部表达导致CD8+ T细胞浸润显著增加。CD8+ T细胞比例的增加仅在肿瘤局部观察到，在肿瘤引流淋巴结中未观察到。耗竭研究表明，GITR-L介导的抗肿瘤生长保护作用需要CD8+ T细胞而非CD4+ T细胞。这些研究表明，肿瘤微环境中GITR-L与GITR之间的信号传导促进了CD8+ T细胞的浸润，而CD8+ T细胞对于控制肿瘤生长至关重要。
