Weil-Hillman G, Schell K, Segal D M, Hank J A, Sosman J A, Sondel P M
Department of Human Oncology, University of Wisconsin, Madison.
J Immunother (1991). 1991 Aug;10(4):267-77. doi: 10.1097/00002371-199108000-00005.
The role of activated T cells in the mediation of antitumor responses has been documented in several experimental models. In some of these, interleukin-2 (IL-2) has been used as a means to induce and expand the antitumor effects of the T cells. IL-2 has been tested in clinical trials for cancer treatment. Surprisingly, T cells appear to be inactivated by IL-2 in these clinical trials. T cells obtained from peripheral blood after IL-2 therapy showed decreased responses to mitogens and alloantigens, did not proliferate in vitro in response to IL-2, and did not mediate non-major histocompatibility complex-restricted cytotoxicity or targeted lysis in the presence of bispecific monoclonal antibodies. In this study, we present evidence that these post-IL-2 therapy T cells are not irreversibly inactivated; they can be activated in vitro by anti-CD3 monoclonal antibody together with IL-2 to upregulate the p55 component of the IL-2 receptor and proliferate. Nevertheless, following activation by anti-CD3 and IL-2, the level of targeted T-cell cytotoxicity mediated by the post-IL-2 therapy T cells was significantly lower than that by pre-IL-2 therapy T cells. Although in vivo treatment with IL-2 alone induces natural killer (NK) cells to mediate lymphokine-activated killer activity, these data suggest that the T-cell lytic function is inhibited by this treatment and only partially reversible by subsequent T-cell receptor activation using anti-CD3 mAb. Exposure of T cells to anti-CD3 mAb prior to in vivo IL-2 treatment generates T-cell lytic activity in vitro. These results, together with preclinical murine studies, suggest that a combined in vivo protocol of anti-CD3 mAb and IL-2, starting first with the anti-CD3 mAb, may cause activation of the T cells in addition to the activation of NK cells and thus warrant clinical testing.
活化T细胞在介导抗肿瘤反应中的作用已在多个实验模型中得到证实。在其中一些模型中，白细胞介素-2（IL-2）已被用作诱导和扩大T细胞抗肿瘤作用的手段。IL-2已在癌症治疗的临床试验中进行了测试。令人惊讶的是，在这些临床试验中，T细胞似乎被IL-2失活。IL-2治疗后从外周血中获得的T细胞对丝裂原和同种异体抗原的反应降低，在体外对IL-2无增殖反应，并且在双特异性单克隆抗体存在下不介导非主要组织相容性复合体限制的细胞毒性或靶向裂解。在本研究中，我们提供证据表明，这些IL-2治疗后的T细胞并非不可逆转地失活；它们可以在体外被抗CD3单克隆抗体与IL-2共同激活，以上调IL-2受体的p55成分并增殖。然而，在被抗CD3和IL-2激活后，IL-2治疗后T细胞介导的靶向T细胞细胞毒性水平明显低于IL-2治疗前T细胞。尽管单独用IL-2进行体内治疗可诱导自然杀伤（NK）细胞介导淋巴因子激活的杀伤活性，但这些数据表明，这种治疗会抑制T细胞的裂解功能，并且仅通过随后使用抗CD3 mAb激活T细胞受体才能部分逆转。在体内IL-2治疗前将T细胞暴露于抗CD3 mAb可在体外产生T细胞裂解活性。这些结果与临床前小鼠研究一起表明，一种先使用抗CD3 mAb的抗CD3 mAb和IL-2联合体内方案，除了激活NK细胞外，还可能导致T细胞激活，因此值得进行临床试验。
