Tanaka Y, Mine S, Hanagiri T, Hiraga T, Morimoto I, Figdor C G, van Kooyk Y, Ozawa H, Nakamura T, Yasumoto K, Eto S
First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu.
Cancer Res. 1998 Sep 15;58(18):4138-45.
Tumor-reactive T cells, known as tumor-infiltrating lymphocyte(TIL)s are known to infiltrate various tumors. Although TILs exert cytotoxic activities against tumor cells, only a small percentage of tumors usually contain TILs that specifically react to tumor antigens. Because the exact role of these lymphocytes is unclear, we investigated the mechanisms of migration and adhesion of TILs to bone metastatic tumors, particularly to osteoblasts and bone marrow-derived stromal cell(BMSC)s. Histopathological examination showed that most TILs in secondary bone metastatic tumors (from primary tumors in the lung or breast) were found in the supporting tissue stroma between the bone and tumor mass. Cultured TILs (obtained from breast tumors) adhered spontaneously to osteoblasts and BMSCs (obtained from patients with osteoarthritis) without exogenous stimulation. Adhesion was further enhanced by chemokines macrophage inflammatory protein (MIP)-1alpha and MIP-1beta. TILs highly expressed activation antigens CD25 and CD69. A spontaneous activation of an integrin, lymphocyte function-associated antigen-1 (LFA-1), was also detected on TILs. TILs produced high concentrations of MIP-1alpha and MIP-1beta and spontaneous polymerization of cytoskeletal F-actin was observed in these cells. Adhesion of TILs to osteoblasts and BMSCs via LFA-1 and very late antigen-4 was associated with the production of osteoclastogen interleukin 6 by the latter cells. Our results indicate that integrins on TILs are activated in an autocrine manner by MIP-1alpha and MIP-1beta, and that treatment with the chemokines increases the binding of TILs on osteoblasts and stromal cells via a mechanism involving intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 as targets for the integrin. Our data also indicated that interactions between TILs and osteoblasts/stromal cells lead to the secretion by the latter of the osteoclastogenic cytokine interleukin 6.
肿瘤反应性T细胞，即肿瘤浸润淋巴细胞（TIL），已知可浸润各种肿瘤。尽管TIL对肿瘤细胞具有细胞毒性活性，但通常只有一小部分肿瘤含有能特异性反应肿瘤抗原的TIL。由于这些淋巴细胞的确切作用尚不清楚，我们研究了TIL向骨转移性肿瘤，特别是向成骨细胞和骨髓来源的基质细胞（BMSC）迁移和黏附的机制。组织病理学检查显示，继发性骨转移性肿瘤（源自肺或乳腺的原发性肿瘤）中的大多数TIL存在于骨与肿瘤块之间的支持组织基质中。培养的TIL（从乳腺肿瘤中获得）在无外源性刺激的情况下可自发黏附于成骨细胞和BMSC（从骨关节炎患者中获得）。趋化因子巨噬细胞炎性蛋白（MIP）-1α和MIP-1β可进一步增强黏附。TIL高表达活化抗原CD25和CD69。在TIL上还检测到整合素淋巴细胞功能相关抗原-1（LFA-1）的自发活化。TIL产生高浓度的MIP-1α和MIP-1β，并且在这些细胞中观察到细胞骨架F-肌动蛋白的自发聚合。TIL通过LFA-1和极晚期抗原-4与成骨细胞和BMSC的黏附与后者细胞产生破骨细胞生成白细胞介素6有关。我们的结果表明，TIL上的整合素通过MIP-1α和MIP-1β以自分泌方式被激活，并且趋化因子处理通过涉及细胞间黏附分子-1和血管细胞黏附分子-1作为整合素靶点的机制增加了TIL与成骨细胞和基质细胞的结合。我们的数据还表明，TIL与成骨细胞/基质细胞之间的相互作用导致后者分泌破骨细胞生成细胞因子白细胞介素6。
