Farrar J D, Katz K H, Windsor J, Thrush G, Scheuermann R H, Uhr J W, Street N E
Graduate Program in Immunology, Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
J Immunol. 1999 Mar 1;162(5):2842-9.
Dormant tumor cells resistant to ablative cancer therapy represent a significant clinical obstacle due to later relapse. Experimentally, the murine B cell lymphoma (BCL1) is used as a model of tumor dormancy in mice vaccinated with the BCL1 Ig. Here, we used this model to explore the cellular mechanisms underlying dormancy. Our previous studies have demonstrated that T cell-mediated immunity is an important component in the regulation of tumor dormancy because Id-immune T cells adoptively transferred into passively immunized SCID mice challenged with BCL1 cells significantly increased the incidence and duration of the dormant state. We have extended these observations and demonstrate that CD8+, but not CD4+, T cells are required for the maintenance of dormancy in BCL1 Ig-immunized BALB/c mice. In parallel studies, the transfer of Id-immune CD8+ cells, but not Id-immune CD4+ cells, conferred significant protection to SCID mice passively immunized with nonprotective levels of polyclonal anti-Id and then challenged with BCL1 cells. Furthermore, the ability of CD8+ T cells to induce a state of dormancy in passively immunized SCID mice was completely abrogated by treatment with neutralizing alpha-IFN-gamma mAbs in vivo. In vitro studies demonstrated that IFN-gamma alone or in combination with reagents to cross-link the surface Ig induced both cell cycle arrest and apoptosis in a BCL1 cell line. Collectively, these data demonstrate a role for CD8+ T cells via endogenous production of IFN-gamma in collaboration with humoral immunity to both induce and maintain a state of tumor dormancy.
对消融性癌症治疗有抗性的休眠肿瘤细胞因后期复发而成为一个重大的临床障碍。在实验中，小鼠B细胞淋巴瘤（BCL1）被用作接种BCL1 Ig的小鼠肿瘤休眠模型。在此，我们利用该模型探索休眠背后的细胞机制。我们之前的研究表明，T细胞介导的免疫是肿瘤休眠调节中的一个重要组成部分，因为将Id免疫T细胞过继转移到用BCL1细胞攻击的被动免疫SCID小鼠中，显著增加了休眠状态的发生率和持续时间。我们扩展了这些观察结果，并证明在接种BCL1 Ig的BALB/c小鼠中，维持休眠需要CD8⁺而非CD4⁺ T细胞。在平行研究中，转移Id免疫CD8⁺细胞而非Id免疫CD4⁺细胞，能为用非保护性水平的多克隆抗Id被动免疫然后用BCL1细胞攻击的SCID小鼠提供显著保护。此外，在体内用中和性α-IFN-γ单克隆抗体处理可完全消除CD8⁺ T细胞在被动免疫SCID小鼠中诱导休眠状态的能力。体外研究表明，单独的IFN-γ或与交联表面Ig的试剂联合使用，可诱导BCL1细胞系中的细胞周期停滞和凋亡。总体而言，这些数据证明了CD8⁺ T细胞通过内源性产生IFN-γ并与体液免疫协作，在诱导和维持肿瘤休眠状态中发挥作用。
