Inoue M, Plautz G E, Shu S
Center for Surgery Research, The Cleveland Clinic Foundation, Ohio 44195, USA.
Cancer Res. 1996 Oct 15;56(20):4702-8.
Adoptive transfer of tumor-sensitized T lymphocytes has demonstrated therapeutic efficacy in animal tumor models and in some patients with melanoma and renal cell cancers. In experimental settings, T lymphocytes derived from lymph nodes (LNs) draining progressively growing tumors can be activated ex vivo to generate tumor-reactive lymphocytes with therapeutic efficacy. Despite the theoretical concern regarding inaccessibility of the central nervous system to systemically transferred T cells, our recent experiments demonstrated that anti-CD3-activated tumor-draining LN cells are capable of mediating the regression of established intracerebral tumors. In this study, several staphylococcal enterotoxins (SEs), including SEA, SEC2, and SEE, and exfoliating toxin, known to be superantigens, were tested for their ability to stimulate tumor-draining LN cells to acquire antitumor reactivity for the treatment of intracerebral tumors. SEs bind to the MHC class II molecule and provide an activating signal to T cells bearing particular T-cell receptor Vbeta chains. Tumor-draining LN cells activated with SEs demonstrated selective Vbeta T-cell expansion. In adoptive immunotherapy of intracranial (IC) tumors, SEA-and SEC2-activated cells had the highest efficacy, whereas SEE-activated cells were not therapeutic. Despite the antigen independence of SE activation, the T cells retained immunological specificity for the tumor, which provided the initial in vivo sensitization of the LN. During the ex vivo stimulation with superantigens, both CD4+ and CD8+ T cells proliferated, and both subsets were required to mediate regression of IC tumors. In contrast to the adoptive immunotherapy of visceral tumors, the systemic administration of exogenous interleukin 2 failed to support the antitumor reactivity in mice depleted of CD4 cells, and, in fact, it inhibited the therapeutic efficacy. Furthermore, mice cured of intracerebral tumors by the adoptive transfer of T cells were resistant to an IC tumor rechallenge. However, in contrast to the immunological specificity demonstrated during the primary adoptive transfer, cured mice were able to reject challenge with several immunologically distinct fibrosarcomas but not a melanoma. These results indicate that superantigen-activated LN cells can circulate to and interact with intracerebral tumors mediating tumor regression in an immunologically specific manner. Although conditions that optimize the treatment of intracerebral tumors appear to be different from those for visceral tumors, analysis of T-cell receptor Vbeta expression among cells activated with several superantigens does not reflect a preferential usage of Vbeta gene segments in the immune response to autochthonous tumors.
肿瘤致敏T淋巴细胞的过继转移已在动物肿瘤模型以及一些黑色素瘤和肾细胞癌患者中显示出治疗效果。在实验环境中，源自引流逐渐生长肿瘤的淋巴结（LN）的T淋巴细胞可在体外被激活，以产生具有治疗效果的肿瘤反应性淋巴细胞。尽管存在关于全身转移的T细胞无法进入中枢神经系统的理论担忧，但我们最近的实验表明，抗CD3激活的肿瘤引流LN细胞能够介导已建立的脑内肿瘤的消退。在本研究中，测试了几种已知为超抗原的葡萄球菌肠毒素（SEs），包括SEA、SEC2和SEE，以及剥脱毒素，以评估它们刺激肿瘤引流LN细胞获得抗肿瘤反应性以治疗脑内肿瘤的能力。SEs与MHC II类分子结合，并为携带特定T细胞受体Vβ链的T细胞提供激活信号。用SEs激活的肿瘤引流LN细胞表现出选择性Vβ T细胞扩增。在颅内（IC）肿瘤的过继免疫治疗中，SEA和SEC2激活的细胞具有最高疗效，而SEE激活的细胞则无治疗作用。尽管SE激活不依赖抗原，但T细胞对肿瘤保留免疫特异性，这为LN提供了初始体内致敏。在用超抗原进行体外刺激期间，CD4+和CD8+ T细胞均增殖，且两个亚群均是介导IC肿瘤消退所必需的。与内脏肿瘤的过继免疫治疗相反，全身性给予外源性白细胞介素2未能支持CD4细胞耗竭小鼠的抗肿瘤反应性，事实上，它还抑制了治疗效果。此外，通过T细胞过继转移治愈脑内肿瘤的小鼠对IC肿瘤再次攻击具有抗性。然而，与初次过继转移期间显示的免疫特异性相反，治愈的小鼠能够排斥几种免疫上不同的纤维肉瘤的攻击，但不能排斥黑色素瘤的攻击。这些结果表明，超抗原激活的LN细胞可循环至脑内肿瘤并与之相互作用，以免疫特异性方式介导肿瘤消退。尽管优化脑内肿瘤治疗的条件似乎与内脏肿瘤不同，但对几种超抗原激活的细胞之间T细胞受体Vβ表达的分析并未反映出在对自身肿瘤的免疫反应中Vβ基因片段的优先使用情况。
