Sharma S, Stolina M, Luo J, Strieter R M, Burdick M, Zhu L X, Batra R K, Dubinett S M
University of California, Los Angeles, Medical School-Wadsworth Pulmonary Laboratory, Veterans Administration West Los Angeles Healthcare Center, CA 90073, USA.
J Immunol. 2000 May 1;164(9):4558-63. doi: 10.4049/jimmunol.164.9.4558.
Secondary lymphoid tissue chemokine (SLC, also referred to as Exodus 2 or 6Ckine) is a recently identified high endothelial-derived CC chemokine. The ability of SLC to chemoattract both Th1 lymphocytes and dendritic cells formed the rationale to evaluate this chemokine in cancer immunotherapy. Intratumoral injection of recombinant SLC evidenced potent antitumor responses and led to complete tumor eradication in 40% of treated mice. SLC-mediated antitumor responses were lymphocyte dependent as evidenced by the fact that this therapy did not alter tumor growth in SCID mice. Studies performed in CD4 and CD8 knockout mice also revealed a requirement for both CD4 and CD8 lymphocyte subsets for SLC-mediated tumor regression. In immunocompetent mice, intratumoral SLC injection led to a significant increase in CD4 and CD8 T lymphocytes and dendritic cells, infiltrating both the tumor and the draining lymph nodes. These cell infiltrates were accompanied by the enhanced elaboration of Th1 cytokines and chemokines monokine induced by IFN-gamma and IFN-gamma-inducible protein 10 but a concomitant decrease in immunosuppressive cytokines at the tumor site. In response to irradiated autologous tumor, splenic and lymph node-derived cells from SLC-treated tumor-bearing mice secreted significantly more IFN-gamma, GM-CSF, and IL-12 and reduced levels of IL-10 than did diluent-treated tumor-bearing mice. After stimulation with irradiated autologous tumor, lymph node-derived lymphocytes from SLC-treated tumor-bearing mice demonstrated enhanced cytolytic capacity, suggesting the generation of systemic immune responses. These findings provide a strong rationale for further evaluation of SLC in tumor immunity and its use in cancer immunotherapy.
二级淋巴组织趋化因子（SLC，也称为Exodus 2或6Ckine）是一种最近发现的由高内皮细胞衍生的CC趋化因子。SLC对Th1淋巴细胞和树突状细胞均具有化学趋化能力，这构成了在癌症免疫治疗中评估这种趋化因子的理论基础。瘤内注射重组SLC显示出强大的抗肿瘤反应，并使40%的受试小鼠肿瘤完全消退。SLC介导的抗肿瘤反应依赖于淋巴细胞，这一事实表明该疗法不会改变SCID小鼠的肿瘤生长。在CD4和CD8基因敲除小鼠中进行的研究还表明，SLC介导的肿瘤消退需要CD4和CD8淋巴细胞亚群。在免疫功能正常的小鼠中，瘤内注射SLC导致肿瘤和引流淋巴结中浸润的CD4和CD8 T淋巴细胞以及树突状细胞显著增加。这些细胞浸润伴随着肿瘤部位Th1细胞因子和趋化因子γ干扰素诱导的单核因子以及γ干扰素诱导蛋白10的分泌增强，但免疫抑制细胞因子水平同时降低。对于经辐照的自体肿瘤，与用稀释剂处理的荷瘤小鼠相比，来自接受SLC治疗的荷瘤小鼠的脾脏和淋巴结来源的细胞分泌的γ干扰素、粒细胞-巨噬细胞集落刺激因子和白细胞介素-12显著更多，而白细胞介素-10水平降低。在用经辐照的自体肿瘤刺激后，来自接受SLC治疗的荷瘤小鼠的淋巴结来源的淋巴细胞表现出增强的细胞溶解能力，表明产生了全身免疫反应。这些发现为进一步评估SLC在肿瘤免疫中的作用及其在癌症免疫治疗中的应用提供了有力的理论依据。
